M. Murdocca, I. Romeo, Gennaro Citro, A. Latini, F. Centofanti, A. Bugatti, F. Caccuri, Arnaldo Caruso, F. Ortuso, Stefano Alcaro, Federica Sangiuolo, Giuseppe Novelli
Genomic surveillance based on sequencing the entire genetic code of SARS-CoV-2 involves monitoring and studying genetic changes and variations in disease-causing organisms such as viruses and bacteria. By tracing the virus, it is possible to prevent epidemic spread in the community, ensuring a ‘precision public health’ strategy. A peptide-based design was applied to provide an efficacious strategy that is able to counteract any emerging viral variant of concern dynamically and promptly to affect the outcomes of a pandemic at an early stage while waiting for the production of the anti-variant-specific vaccine, which require longer times. The inhibition of the interaction between the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and one of the cellular receptors (DPP4) that its receptors routinely bind to infect human cells is an intriguing therapeutic approach to prevent the virus from entering human cells. Among the other modalities developed for this purpose, peptides surely offer unique advantages, including ease of synthesis, serum stability, low immunogenicity and toxicity, and small production and distribution chain costs. Here, we obtained a potent new inhibitor based on the rearrangement of a previously identified peptide that has been rationally designed on a cell dipeptidyl peptidase 4 (DPP4) sequence, a ubiquitous membrane protein known to bind the RBD-SPIKE domain of the virus. This novel peptide (named DPP4-derived), conceived as an endogenous “drug”, is capable of targeting the latest tested variants with a high affinity, reducing the VSV* DG-Fluc pseudovirus Omicron’s infection capacity by up to 14%, as revealed by in vitro testing in human Calu-3 cells. Surface plasmon resonance (SPR) confirmed the binding affinity of the new DPP4-derived peptide with Omicron variant RBD.
{"title":"A Dynamic and Effective Peptide-Based Strategy for Promptly Addressing Emerging SARS-CoV-2 Variants of Concern","authors":"M. Murdocca, I. Romeo, Gennaro Citro, A. Latini, F. Centofanti, A. Bugatti, F. Caccuri, Arnaldo Caruso, F. Ortuso, Stefano Alcaro, Federica Sangiuolo, Giuseppe Novelli","doi":"10.3390/ph17070891","DOIUrl":"https://doi.org/10.3390/ph17070891","url":null,"abstract":"Genomic surveillance based on sequencing the entire genetic code of SARS-CoV-2 involves monitoring and studying genetic changes and variations in disease-causing organisms such as viruses and bacteria. By tracing the virus, it is possible to prevent epidemic spread in the community, ensuring a ‘precision public health’ strategy. A peptide-based design was applied to provide an efficacious strategy that is able to counteract any emerging viral variant of concern dynamically and promptly to affect the outcomes of a pandemic at an early stage while waiting for the production of the anti-variant-specific vaccine, which require longer times. The inhibition of the interaction between the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and one of the cellular receptors (DPP4) that its receptors routinely bind to infect human cells is an intriguing therapeutic approach to prevent the virus from entering human cells. Among the other modalities developed for this purpose, peptides surely offer unique advantages, including ease of synthesis, serum stability, low immunogenicity and toxicity, and small production and distribution chain costs. Here, we obtained a potent new inhibitor based on the rearrangement of a previously identified peptide that has been rationally designed on a cell dipeptidyl peptidase 4 (DPP4) sequence, a ubiquitous membrane protein known to bind the RBD-SPIKE domain of the virus. This novel peptide (named DPP4-derived), conceived as an endogenous “drug”, is capable of targeting the latest tested variants with a high affinity, reducing the VSV* DG-Fluc pseudovirus Omicron’s infection capacity by up to 14%, as revealed by in vitro testing in human Calu-3 cells. Surface plasmon resonance (SPR) confirmed the binding affinity of the new DPP4-derived peptide with Omicron variant RBD.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141678139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Kollipara, Frederico Martins, Rebeka Jereb, Dejan Krajcar, Tausif Ahmed
Bioequivalence studies are pivotal in generic drug development wherein therapeutic equivalence is provided with an innovator product. However, bioequivalence studies represent significant complexities due to the interplay of multiple factors related to drug, formulation, physiology, and pharmacokinetics. Approaches such as physiologically based biopharmaceutics modeling (PBBM) can enable virtual bioequivalence (VBE) assessment through appropriately developed and validated models. Such models are now being extensively used for bioequivalence risk assessment, internal decision-making, and the evaluation of drug and formulation factors related to bioequivalence. Depiction of the above-mentioned factors through the incorporation of variability and development of a virtual population for bioequivalence assessment is of paramount importance in utilizing such models. In this manuscript, we have portrayed our current understanding of VBE. A detailed explanation was provided with respect to study designs, in vivo variability, and the impact of physiological, drug, and formulation factors on the development of the population for VBE. Furthermore, strategies are suggested to incorporate variability in GastroPlus with an emphasis on intra-subject and inter-occasion variability. Two industrial case studies pertaining to immediate and modified release formulation were portrayed wherein VBE was utilized for decision-making and regulatory justification. Finally, regulatory understanding in the area of VBE, along with future perspectives, was detailed.
{"title":"Advancing Virtual Bioequivalence for Orally Administered Drug Products: Methodology, Real-World Applications and Future Outlook","authors":"S. Kollipara, Frederico Martins, Rebeka Jereb, Dejan Krajcar, Tausif Ahmed","doi":"10.3390/ph17070876","DOIUrl":"https://doi.org/10.3390/ph17070876","url":null,"abstract":"Bioequivalence studies are pivotal in generic drug development wherein therapeutic equivalence is provided with an innovator product. However, bioequivalence studies represent significant complexities due to the interplay of multiple factors related to drug, formulation, physiology, and pharmacokinetics. Approaches such as physiologically based biopharmaceutics modeling (PBBM) can enable virtual bioequivalence (VBE) assessment through appropriately developed and validated models. Such models are now being extensively used for bioequivalence risk assessment, internal decision-making, and the evaluation of drug and formulation factors related to bioequivalence. Depiction of the above-mentioned factors through the incorporation of variability and development of a virtual population for bioequivalence assessment is of paramount importance in utilizing such models. In this manuscript, we have portrayed our current understanding of VBE. A detailed explanation was provided with respect to study designs, in vivo variability, and the impact of physiological, drug, and formulation factors on the development of the population for VBE. Furthermore, strategies are suggested to incorporate variability in GastroPlus with an emphasis on intra-subject and inter-occasion variability. Two industrial case studies pertaining to immediate and modified release formulation were portrayed wherein VBE was utilized for decision-making and regulatory justification. Finally, regulatory understanding in the area of VBE, along with future perspectives, was detailed.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"105 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141682807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Derek J. Overstreet, Gabriel Zdrale, Alex C. McLaren
Effective treatment of postoperative pain lasting for multiple days without opioids is an important clinical need. We previously reported analgesia lasting up to 96 h in a porcine soft tissue model of postoperative pain using SBG004, an extended-release formulation of bupivacaine based on the temperature-responsive polymer poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ]. Orthopaedic surgical sites such as the knee can involve complex sensory innervation which presents a distinct challenge to local anesthetic delivery. The purpose of this work was to evaluate the pharmacokinetics and efficacy of SBG004 in an orthopaedic surgical model in comparison to currently available local anesthetics. Pharmacokinetics following periarticular (PA) or intraarticular (IA) injection of SBG004 were compared against liposomal bupivacaine (Lip-Bupi) PA in New Zealand White rabbits (all doses 14.5 mg/kg). Analgesic efficacy of SBG004 (IA, PA, or IA + PA), three active comparators, and saline was evaluated following knee surgery in New Zealand White rabbits. Analgesia was assessed via weight-bearing on the operated limb during spontaneous large steps in video recordings. Systemic bupivacaine exposure lasted at least 7 days for SBG004 PA, 4 days for SBG004 IA, and 2 days for Lip-Bupi PA. In the analgesia study, weight-bearing in all active groups except SBG004 IA was more frequent versus saline through 8 h postoperatively (p < 0.05). Only SBG004 IA + PA resulted in a higher proportion of weight-bearing rabbits at 24 h versus saline (6/7 versus 2/10, p = 0.015). Analysis of pooled data from 24–72 h showed significantly greater frequency of weight-bearing in rabbits receiving SBG004 IA + PA (71%) versus saline (37%), ropivacaine cocktail (41%), and Lip-Bupi PA (36%). The results indicate that the release profile from SBG004 PA or IA coincides reasonably with the time course of postoperative pain, and SBG004 may produce longer duration of analgesia than local anesthetics currently used in knee surgery, including during the period of 24–72 h recognized as a target for extended-release local anesthetics.
在不使用阿片类药物的情况下有效治疗持续多天的术后疼痛是一项重要的临床需求。SBG004 是布比卡因的缓释制剂，基于温度响应聚合物聚（N-异丙基丙烯酰胺-共二甲基丁内酯丙烯酰胺-共Jeffamine M-1000丙烯酰胺）[PNDJ]。膝关节等骨科手术部位可能涉及复杂的感觉神经支配，这给局部麻醉剂的给药带来了独特的挑战。这项研究的目的是评估 SBG004 在骨科手术模型中与现有局麻药相比的药代动力学和疗效。在新西兰白兔（所有剂量均为 14.5 毫克/千克）中，比较了关节周围（PA）或关节内（IA）注射 SBG004 与脂质体布比卡因（Lip-Bupi）PA 后的药代动力学。在新西兰白兔进行膝关节手术后，对 SBG004（IA、PA 或 IA + PA）、三种活性比较药和生理盐水的镇痛效果进行了评估。在视频记录中，通过手术肢体在自发大步行走过程中的负重来评估镇痛效果。全身布比卡因暴露持续时间：SBG004 PA 至少 7 天，SBG004 IA 至少 4 天，Lip-Bupi PA 至少 2 天。在镇痛研究中，除 SBG004 IA 外，所有活动组术后 8 小时内的负重次数均高于生理盐水组（P < 0.05）。只有 SBG004 IA + PA 组与生理盐水组相比，在术后 24 小时内负重的兔子比例更高（6/7 对 2/10，p = 0.015）。对 24-72 小时的汇总数据进行分析后发现，接受 SBG004 IA + PA（71%）的兔子负重的比例明显高于生理盐水（37%）、罗哌卡因鸡尾酒（41%）和 Lip-Bupi PA（36%）。研究结果表明，SBG004 PA 或 IA 的释放曲线与术后疼痛的时间过程相当吻合，与目前膝关节手术中使用的局麻药相比，SBG004 可产生更长的镇痛时间，包括在 24-72 小时内，这段时间被认为是缓释局麻药的目标时间。
{"title":"Extended Release of Bupivacaine from Temperature-Responsive PNDJ Hydrogels Improves Postoperative Weight-Bearing in Rabbits Following Knee Surgery","authors":"Derek J. Overstreet, Gabriel Zdrale, Alex C. McLaren","doi":"10.3390/ph17070879","DOIUrl":"https://doi.org/10.3390/ph17070879","url":null,"abstract":"Effective treatment of postoperative pain lasting for multiple days without opioids is an important clinical need. We previously reported analgesia lasting up to 96 h in a porcine soft tissue model of postoperative pain using SBG004, an extended-release formulation of bupivacaine based on the temperature-responsive polymer poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ]. Orthopaedic surgical sites such as the knee can involve complex sensory innervation which presents a distinct challenge to local anesthetic delivery. The purpose of this work was to evaluate the pharmacokinetics and efficacy of SBG004 in an orthopaedic surgical model in comparison to currently available local anesthetics. Pharmacokinetics following periarticular (PA) or intraarticular (IA) injection of SBG004 were compared against liposomal bupivacaine (Lip-Bupi) PA in New Zealand White rabbits (all doses 14.5 mg/kg). Analgesic efficacy of SBG004 (IA, PA, or IA + PA), three active comparators, and saline was evaluated following knee surgery in New Zealand White rabbits. Analgesia was assessed via weight-bearing on the operated limb during spontaneous large steps in video recordings. Systemic bupivacaine exposure lasted at least 7 days for SBG004 PA, 4 days for SBG004 IA, and 2 days for Lip-Bupi PA. In the analgesia study, weight-bearing in all active groups except SBG004 IA was more frequent versus saline through 8 h postoperatively (p < 0.05). Only SBG004 IA + PA resulted in a higher proportion of weight-bearing rabbits at 24 h versus saline (6/7 versus 2/10, p = 0.015). Analysis of pooled data from 24–72 h showed significantly greater frequency of weight-bearing in rabbits receiving SBG004 IA + PA (71%) versus saline (37%), ropivacaine cocktail (41%), and Lip-Bupi PA (36%). The results indicate that the release profile from SBG004 PA or IA coincides reasonably with the time course of postoperative pain, and SBG004 may produce longer duration of analgesia than local anesthetics currently used in knee surgery, including during the period of 24–72 h recognized as a target for extended-release local anesthetics.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":" 27","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141680383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
O. Khoumeri, S. Hutter, N. Primas, C. Castera-Ducros, Sandra Carvalho, Susan Wyllie, M. Efrit, Dimitri Fayolle, M. Since, Patrice Vanelle, P. Verhaeghe, N. Azas, Hussein El-Kashef
A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.
{"title":"Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential","authors":"O. Khoumeri, S. Hutter, N. Primas, C. Castera-Ducros, Sandra Carvalho, Susan Wyllie, M. Efrit, Dimitri Fayolle, M. Since, Patrice Vanelle, P. Verhaeghe, N. Azas, Hussein El-Kashef","doi":"10.3390/ph17070878","DOIUrl":"https://doi.org/10.3390/ph17070878","url":null,"abstract":"A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"82 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141682962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seong-Kyu Kim, J. Choe, Ji-Won Kim, Ki-Yeun Park, Boyoung Kim
Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.
{"title":"Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages","authors":"Seong-Kyu Kim, J. Choe, Ji-Won Kim, Ki-Yeun Park, Boyoung Kim","doi":"10.3390/ph17070883","DOIUrl":"https://doi.org/10.3390/ph17070883","url":null,"abstract":"Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"9 s4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141681363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hanna Dib, Mahmoud Abu-samha, K. Younes, Mohamed A. O. Abdelfattah
In this study, we evaluated the physicochemical properties related to the previously reported anticancer activity of a dataset comprising thirty 1,2-dihydropyridine derivatives. We utilized Principal Component Analysis (PCA) to identify the most significant influencing factors. The PCA analysis showed that the first two principal components accounted for 59.91% of the total variance, indicating a strong correlation between the molecules and specific descriptors. Among the 239 descriptors analyzed, 18 were positively correlated with anticancer activity, clustering with the 12 most active compounds based on their IC50 values. Six of these variables—LogP, Csp3, b_1rotN, LogS, TPSA, and lip_don—are related to drug-likeness potential. Thus, we then ranked the 12 compounds according to these six variables and excluded those violating the drug-likeness criteria, resulting in a shortlist of nine compounds. Next, we investigated the binding affinity of these nine shortlisted compounds with the use of molecular docking towards the PIM-1 Kinase enzyme (PDB: 2OBJ), which is overexpressed in various cancer cells. Compound 6 exhibited the best docking score among the docked compounds, with a docking score of −11.77 kcal/mol, compared to −12.08 kcal/mol for the reference PIM-1 kinase inhibitor, 6-(5-bromo-2-hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile. To discover new PIM-1 kinase inhibitors, we designed nine novel compounds featuring hybrid structures of compound 6 and the reference inhibitor. Among these, compound 31 displayed the best binding affinity, with a docking score of −13.11 kcal/mol. Additionally, we performed PubChem database mining using the structure of compound 6 and the similarity search tool, identifying 16 structurally related compounds with various reported biological properties. Among these, compound 52 exhibited the best binding affinity, with a docking score of −13.03 kcal/mol. Finally, molecular dynamics (MD) studies were conducted to confirm the stability of the protein–ligand complexes obtained from docking the studied compounds to PIM-1 kinase, validating the potential of these compounds as PIM-1 kinase inhibitors.
{"title":"Evaluating the Physicochemical Properties–Activity Relationship and Discovering New 1,2-Dihydropyridine Derivatives as Promising Inhibitors for PIM1-Kinase: Evidence from Principal Component Analysis, Molecular Docking, and Molecular Dynamics Studies","authors":"Hanna Dib, Mahmoud Abu-samha, K. Younes, Mohamed A. O. Abdelfattah","doi":"10.3390/ph17070880","DOIUrl":"https://doi.org/10.3390/ph17070880","url":null,"abstract":"In this study, we evaluated the physicochemical properties related to the previously reported anticancer activity of a dataset comprising thirty 1,2-dihydropyridine derivatives. We utilized Principal Component Analysis (PCA) to identify the most significant influencing factors. The PCA analysis showed that the first two principal components accounted for 59.91% of the total variance, indicating a strong correlation between the molecules and specific descriptors. Among the 239 descriptors analyzed, 18 were positively correlated with anticancer activity, clustering with the 12 most active compounds based on their IC50 values. Six of these variables—LogP, Csp3, b_1rotN, LogS, TPSA, and lip_don—are related to drug-likeness potential. Thus, we then ranked the 12 compounds according to these six variables and excluded those violating the drug-likeness criteria, resulting in a shortlist of nine compounds. Next, we investigated the binding affinity of these nine shortlisted compounds with the use of molecular docking towards the PIM-1 Kinase enzyme (PDB: 2OBJ), which is overexpressed in various cancer cells. Compound 6 exhibited the best docking score among the docked compounds, with a docking score of −11.77 kcal/mol, compared to −12.08 kcal/mol for the reference PIM-1 kinase inhibitor, 6-(5-bromo-2-hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile. To discover new PIM-1 kinase inhibitors, we designed nine novel compounds featuring hybrid structures of compound 6 and the reference inhibitor. Among these, compound 31 displayed the best binding affinity, with a docking score of −13.11 kcal/mol. Additionally, we performed PubChem database mining using the structure of compound 6 and the similarity search tool, identifying 16 structurally related compounds with various reported biological properties. Among these, compound 52 exhibited the best binding affinity, with a docking score of −13.03 kcal/mol. Finally, molecular dynamics (MD) studies were conducted to confirm the stability of the protein–ligand complexes obtained from docking the studied compounds to PIM-1 kinase, validating the potential of these compounds as PIM-1 kinase inhibitors.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"5 2‐3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141682505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sharanappa Achappa, N. Aldabaan, S. Desai, Uday M. Muddapur, I. Shaikh, M. Mahnashi, Abdullateef A. Alshehri, B. A. Mannasaheb, A. Khan
The limitations of the current vaccination strategy for the Kyasanur Forest Disease virus (KFDV) underscore the critical need for effective antiviral treatments, highlighting the crucial importance of exploring novel therapeutic approaches through in silico drug design. Kyasanur Forest Disease, caused by KFDV, is a tick-borne disease with a mortality of 3–5% and an annual incidence of 400 to 500 cases. In the early stage of infection, the envelope protein plays a crucial role by facilitating host–virus interactions. The objective of this research is to develop effective antivirals targeting the envelope protein to disrupt the virus–host interaction. In line with this, the 3D structure of the envelope protein was modeled and refined through molecular modeling techniques, and subsequently, ligands were designed via de novo design and pharmacophore screening, yielding 12 potential hits followed by ADMET analysis. The top five candidates underwent geometry optimization and molecular docking. Notably, compounds L4 (SA28) and L3 (CNP0247967) are predicted to have significant binding affinities of −8.91 and −7.58 kcal/mol, respectively, toward the envelope protein, based on computational models. Both compounds demonstrated stability during 200 ns molecular dynamics simulations, and the MM-GBSA binding free-energy values were −85.26 ± 4.63 kcal/mol and −66.60 ± 2.92 kcal/mol for the envelope protein L3 and L4 complexes, respectively. Based on the computational prediction, it is suggested that both compounds have potential as drug candidates for controlling host–virus interactions by targeting the envelope protein. Further validation through in-vitro assays would complement the findings of the present in silico investigations.
{"title":"Computational Exploration of Potential Pharmacological Inhibitors Targeting the Envelope Protein of the Kyasanur Forest Disease Virus","authors":"Sharanappa Achappa, N. Aldabaan, S. Desai, Uday M. Muddapur, I. Shaikh, M. Mahnashi, Abdullateef A. Alshehri, B. A. Mannasaheb, A. Khan","doi":"10.3390/ph17070884","DOIUrl":"https://doi.org/10.3390/ph17070884","url":null,"abstract":"The limitations of the current vaccination strategy for the Kyasanur Forest Disease virus (KFDV) underscore the critical need for effective antiviral treatments, highlighting the crucial importance of exploring novel therapeutic approaches through in silico drug design. Kyasanur Forest Disease, caused by KFDV, is a tick-borne disease with a mortality of 3–5% and an annual incidence of 400 to 500 cases. In the early stage of infection, the envelope protein plays a crucial role by facilitating host–virus interactions. The objective of this research is to develop effective antivirals targeting the envelope protein to disrupt the virus–host interaction. In line with this, the 3D structure of the envelope protein was modeled and refined through molecular modeling techniques, and subsequently, ligands were designed via de novo design and pharmacophore screening, yielding 12 potential hits followed by ADMET analysis. The top five candidates underwent geometry optimization and molecular docking. Notably, compounds L4 (SA28) and L3 (CNP0247967) are predicted to have significant binding affinities of −8.91 and −7.58 kcal/mol, respectively, toward the envelope protein, based on computational models. Both compounds demonstrated stability during 200 ns molecular dynamics simulations, and the MM-GBSA binding free-energy values were −85.26 ± 4.63 kcal/mol and −66.60 ± 2.92 kcal/mol for the envelope protein L3 and L4 complexes, respectively. Based on the computational prediction, it is suggested that both compounds have potential as drug candidates for controlling host–virus interactions by targeting the envelope protein. Further validation through in-vitro assays would complement the findings of the present in silico investigations.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":" 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141681055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wonsuk Shin, Dong Hyeon Lee, H. Yoo, Huiyoung Jung, M. Bang, Anhye Kim
This study investigated the usage patterns and impact of therapeutic drug monitoring (TDM) for risperidone and paliperidone in patients diagnosed with schizophrenia, utilizing retrospective real-world data sourced from a single center’s Clinical Data Warehouse. Our study cohort comprised patients diagnosed with schizophrenia undergoing treatment with either risperidone or paliperidone. Data on demographic characteristics, comorbidities, medication utilization, and clinical outcomes were collected. Patients were categorized into two groups: those undergoing TDM and those not undergoing TDM. Additionally, within the TDM group, patients were further stratified based on their risperidone and paliperidone concentrations relative to the reference range. The findings revealed that patients in the TDM group received higher risperidone and paliperidone doses (320 mg/day and 252 mg/day, p = 0.0045) compared to their non-TDM counterparts. Nevertheless, no significant disparities were observed in hospitalization rates, duration of hospital stays, or compliance between the two groups (p = 0.9082, 0.5861, 0.7516, respectively). Subgroup analysis within the TDM cohort exhibited no notable distinctions in clinical outcomes between patients with concentrations within or surpassing the reference range. Despite the possibility of a selection bias in assigning patients to the groups, this study provides a comprehensive analysis of TDM utilization and its ramifications on schizophrenia treatment outcomes.
{"title":"Assessing the Clinical Efficacy of Therapeutic Drug Monitoring for Risperidone and Paliperidone in Patients with Schizophrenia: Insights from a Clinical Data Warehouse","authors":"Wonsuk Shin, Dong Hyeon Lee, H. Yoo, Huiyoung Jung, M. Bang, Anhye Kim","doi":"10.3390/ph17070882","DOIUrl":"https://doi.org/10.3390/ph17070882","url":null,"abstract":"This study investigated the usage patterns and impact of therapeutic drug monitoring (TDM) for risperidone and paliperidone in patients diagnosed with schizophrenia, utilizing retrospective real-world data sourced from a single center’s Clinical Data Warehouse. Our study cohort comprised patients diagnosed with schizophrenia undergoing treatment with either risperidone or paliperidone. Data on demographic characteristics, comorbidities, medication utilization, and clinical outcomes were collected. Patients were categorized into two groups: those undergoing TDM and those not undergoing TDM. Additionally, within the TDM group, patients were further stratified based on their risperidone and paliperidone concentrations relative to the reference range. The findings revealed that patients in the TDM group received higher risperidone and paliperidone doses (320 mg/day and 252 mg/day, p = 0.0045) compared to their non-TDM counterparts. Nevertheless, no significant disparities were observed in hospitalization rates, duration of hospital stays, or compliance between the two groups (p = 0.9082, 0.5861, 0.7516, respectively). Subgroup analysis within the TDM cohort exhibited no notable distinctions in clinical outcomes between patients with concentrations within or surpassing the reference range. Despite the possibility of a selection bias in assigning patients to the groups, this study provides a comprehensive analysis of TDM utilization and its ramifications on schizophrenia treatment outcomes.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"10 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141681247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Igor Belenichev, V. Ryzhenko, O. Popazova, Nina Bukhtiyarova, Nadia Gorchakova, Valentyn Oksenych, O. Kamyshnyi
For the first time, to optimize the creation of new neuroprotective agents based on bioflavonoids, we applied information technologies; these include docking analysis to calculate the binding of candidate molecules to the pharmacological target protein transthyretin as well as a program of virtual screening of NO scavengers. As a result of this approach, the substance catechin was isolated from candidate molecules—quercetin, catechin, Epicatechin gallate, Epicatechin, Procyanidin B1, Procyanidin B2, Procyanidin B3, and Catechin-3-gallate—according to docking analysis. As a result of virtual screening, catechin was identified as a potential NO scavenger (55.15% prediction). The results of the prediction were confirmed by in vitro experiments. Course administration of catechin to animals with experimental multiple sclerosis (MS) against the background of methylprednisolone administration completely eliminated lethal cases, reduced the number of diseased animals by 20% as well as prevented the development of severe neurological symptoms by 20% (compared to the methylprednisolone group) and by 60% compared to the control group. Course administration of catechin with methylprednisolone leads to a decrease in the neurodegradation markers in the cytosol of rats, with EAE: NSE by 37% and S-100 by 54.8%. The combined administration of methylprednisolone significantly exceeds the combination of methylprednisolone with the reference drug mexidol by the degree of NSE reduction. The obtained results indicate a significant neuroprotective effect of ocular combinations of methylprednisolone and catechin. The above-mentioned confirms the correctness of the bioflavonoid selection with the help of a virtual screening program.
{"title":"Optimization of the Search for Neuroprotectors among Bioflavonoids","authors":"Igor Belenichev, V. Ryzhenko, O. Popazova, Nina Bukhtiyarova, Nadia Gorchakova, Valentyn Oksenych, O. Kamyshnyi","doi":"10.3390/ph17070877","DOIUrl":"https://doi.org/10.3390/ph17070877","url":null,"abstract":"For the first time, to optimize the creation of new neuroprotective agents based on bioflavonoids, we applied information technologies; these include docking analysis to calculate the binding of candidate molecules to the pharmacological target protein transthyretin as well as a program of virtual screening of NO scavengers. As a result of this approach, the substance catechin was isolated from candidate molecules—quercetin, catechin, Epicatechin gallate, Epicatechin, Procyanidin B1, Procyanidin B2, Procyanidin B3, and Catechin-3-gallate—according to docking analysis. As a result of virtual screening, catechin was identified as a potential NO scavenger (55.15% prediction). The results of the prediction were confirmed by in vitro experiments. Course administration of catechin to animals with experimental multiple sclerosis (MS) against the background of methylprednisolone administration completely eliminated lethal cases, reduced the number of diseased animals by 20% as well as prevented the development of severe neurological symptoms by 20% (compared to the methylprednisolone group) and by 60% compared to the control group. Course administration of catechin with methylprednisolone leads to a decrease in the neurodegradation markers in the cytosol of rats, with EAE: NSE by 37% and S-100 by 54.8%. The combined administration of methylprednisolone significantly exceeds the combination of methylprednisolone with the reference drug mexidol by the degree of NSE reduction. The obtained results indicate a significant neuroprotective effect of ocular combinations of methylprednisolone and catechin. The above-mentioned confirms the correctness of the bioflavonoid selection with the help of a virtual screening program.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":" 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141680861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mohan Rao, Eric McDuffie, Sanjay Srivastava, Warren Plaisted, Clifford Sachs
The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.
药物对核受体（NR）活性的意外调节可导致内分泌、胃肠道、肝脏心血管和中枢神经系统中毒。虽然二级药理学筛选试验包括核受体，但人们对小分子药物与核受体意外相互作用导致的安全风险仍然知之甚少。为了确定与 48 种人类表达的 NRs 中的 44 种发生功能性相互作用可能导致的非临床和临床安全效应，我们对科学文献、组织表达数据进行了系统性的叙述性综述，并使用编辑数据库（OFF-X™）（Off-X, Clarivate）以表格和机器可读的格式整理了与 NRs 功能调节相关的毒性报告。在同行评议期刊、监管机构通报、大会/会议、临床试验登记册和公司通报中，与安全警报数量最多的前五种 NR 分别是糖皮质激素受体（GR，18328 例）、雄激素受体（AR，18219 例）、雌激素受体（ER，12028 例）、维甲酸受体（RAR，10450 例）和孕烷 X 受体（PXR，8044 例）。与 NR 调节有关的毒性包括肝毒性、心脏毒性、内分泌紊乱、致癌性、代谢紊乱和神经毒性。这些毒性通常源于过氧化物酶体增殖激活受体（PPARα、PPARγ）、ER、PXR、AR 和 GR 等受体的失调。这种失调会导致各种健康问题，包括肝脏肿大、肝细胞癌、心脏相关问题、内分泌失调、肿瘤生长、代谢综合征和脑功能损伤。利用热图对人类和大鼠组织进行基因表达分析，补充了与报告的毒性相关的 NRs 功能调节。有趣的是，某些 NRs 在以前与毒性无关的组织中显示出普遍表达，这表明有可能利用器官特异性 NR 相互作用达到治疗目的。
{"title":"Safety Implications of Modulating Nuclear Receptors: A Comprehensive Analysis from Non-Clinical and Clinical Perspectives","authors":"Mohan Rao, Eric McDuffie, Sanjay Srivastava, Warren Plaisted, Clifford Sachs","doi":"10.3390/ph17070875","DOIUrl":"https://doi.org/10.3390/ph17070875","url":null,"abstract":"The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.","PeriodicalId":509865,"journal":{"name":"Pharmaceuticals","volume":"47 S227","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141683045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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