Malaria represents a major global health concern, primarily due to the emergence of resistance against most currently available antimalarial drugs. This pressing issue necessitates the discovery of novel antimalarial agents to combat the escalating resistance. A cyclin-dependent kinase (CDK)-like protein, Pfmrk, found in Plasmodium falciparum, plays a crucial role in regulating cell proliferation and exhibits a 36.28% sequence homology with its human counterpart hCDK7. Pfmrk forms a complex with plasmodial cyclin (Pfcyc-1) and stimulates kinase activity. Pfcyc-1 from P. falciparum, with the highest sequence homology to human cyclin (cyclin H), binds and activates Pfmrk in a cyclin-dependent manner. This discovery provides the first indication that cyclin subunits may regulate both human and plasmodial CDKs in a similar fashion. In this study, we conducted molecular docking and simulation analysis to investigate the interaction between Pfmrk and a selection of the FDA-approved drugs retrieved from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap – were screened based on their binding energies, with the best-docked scores ranging between −8 kcal/mol and −12 kcal/mol. Further, evaluation through molecular dynamics simulations for 100 nanoseconds revealed that Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the amino acid residues located in the active site of Pfmrk. The results of the in silico investigation indicate that Lurasidone and Donovex exhibit antimalarial potential and could serve as promising Pfmrk inhibitors. Further, development of new drugs based on these findings warrants subsequent in vitro studies.
{"title":"Drug repurposing approach for identifying Pfmrk inhibitors as potential antimalarial agents: An in silico analysis","authors":"Abhishek Sahu, Tanuj Handa, Debanjan Kundu","doi":"10.36922/itps.1313","DOIUrl":"https://doi.org/10.36922/itps.1313","url":null,"abstract":"Malaria represents a major global health concern, primarily due to the emergence of resistance against most currently available antimalarial drugs. This pressing issue necessitates the discovery of novel antimalarial agents to combat the escalating resistance. A cyclin-dependent kinase (CDK)-like protein, Pfmrk, found in Plasmodium falciparum, plays a crucial role in regulating cell proliferation and exhibits a 36.28% sequence homology with its human counterpart hCDK7. Pfmrk forms a complex with plasmodial cyclin (Pfcyc-1) and stimulates kinase activity. Pfcyc-1 from P. falciparum, with the highest sequence homology to human cyclin (cyclin H), binds and activates Pfmrk in a cyclin-dependent manner. This discovery provides the first indication that cyclin subunits may regulate both human and plasmodial CDKs in a similar fashion. In this study, we conducted molecular docking and simulation analysis to investigate the interaction between Pfmrk and a selection of the FDA-approved drugs retrieved from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap – were screened based on their binding energies, with the best-docked scores ranging between −8 kcal/mol and −12 kcal/mol. Further, evaluation through molecular dynamics simulations for 100 nanoseconds revealed that Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the amino acid residues located in the active site of Pfmrk. The results of the in silico investigation indicate that Lurasidone and Donovex exhibit antimalarial potential and could serve as promising Pfmrk inhibitors. Further, development of new drugs based on these findings warrants subsequent in vitro studies.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"93 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135975595","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}
Hanaa Ali Hussein, Fatin L. Khaphi, Zahra Kadhum Saeed
Cyanobacteria are rich in bioactive compounds that exhibit diverse biological activities, including antiproliferative, cytotoxic, and antineoplastic properties. Many of these compounds are currently being studied in clinical trials. In this paper, newly discovered bioactive compounds from various cyanobacteria species that have demonstrated anticancer effects against multiple cancer cell lines, such as apratoxin, symplostatin 1, bartolosides, caylobolide, bisebromoamides, carmaphycins, and anaenamides, are reviewed. At present, there are no clear guidelines on approving cyanobacteria-derived bioactive compounds for use in treating diseases. While it is not uncommon that the intake of these compounds is accompanied by side effects, investigations on these compounds should focus on increasing the safety and efficacy of the compounds, or at least tread a fine line between drug safety and effectiveness for cancer patients. This review overviews the efficacy and cytotoxicity of cyanobacteria-derived bioactive compounds, providing researchers insights into how to maximize the benefits of these compounds through research.
{"title":"Cytotoxicity of bioactive compounds derived from cyanobacteria","authors":"Hanaa Ali Hussein, Fatin L. Khaphi, Zahra Kadhum Saeed","doi":"10.36922/itps.1388","DOIUrl":"https://doi.org/10.36922/itps.1388","url":null,"abstract":"Cyanobacteria are rich in bioactive compounds that exhibit diverse biological activities, including antiproliferative, cytotoxic, and antineoplastic properties. Many of these compounds are currently being studied in clinical trials. In this paper, newly discovered bioactive compounds from various cyanobacteria species that have demonstrated anticancer effects against multiple cancer cell lines, such as apratoxin, symplostatin 1, bartolosides, caylobolide, bisebromoamides, carmaphycins, and anaenamides, are reviewed. At present, there are no clear guidelines on approving cyanobacteria-derived bioactive compounds for use in treating diseases. While it is not uncommon that the intake of these compounds is accompanied by side effects, investigations on these compounds should focus on increasing the safety and efficacy of the compounds, or at least tread a fine line between drug safety and effectiveness for cancer patients. This review overviews the efficacy and cytotoxicity of cyanobacteria-derived bioactive compounds, providing researchers insights into how to maximize the benefits of these compounds through research.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"46 20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134906728","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}
Anjali Patel, Daisy Valle, Drashti Patel, Marco Foreman, Akash Nijhawan, Devon Foster, Alexander Nguyen, Brandon Lucke-Wold
Developing more specialized care for neurological disorders, such as aneurysms, arteriovenous malformations, and strokes, can revolutionize patient healthcare and outcomes. With the advent of surgical techniques such as flow diversion, non-stent- and stent-assisted coiling, and catheter embolization for elective aneurysm treatment in neurological patients, the adverse effects and morbidities associated with aneurysms can be reduced. This paper aims to highlight three specific strengths and weaknesses of the newly emerged techniques. Flow diversion devices involve placing a stent in the parent artery, whereas Woven EndoBridge embolization involves manipulation of the wall of the artery without the administration of dual-antiplatelet therapy. In addition to aneurysm treatment, the administration of antiplatelets and anticoagulants is helpful in disrupting the coagulation cascade. As stated in the new and enhanced guidelines released by the American Heart Association, the administration of dual anticoagulants is beneficial to the patients if they have low ischemic severity. Understanding the various benefits and complications associated with each treatment can allow clinicians to gain insight into the potential trajectory of treatment for different patients.
{"title":"Antiplatelet, anticoagulation, and elective aneurysm treatments in neurological patients","authors":"Anjali Patel, Daisy Valle, Drashti Patel, Marco Foreman, Akash Nijhawan, Devon Foster, Alexander Nguyen, Brandon Lucke-Wold","doi":"10.36922/itps.1202","DOIUrl":"https://doi.org/10.36922/itps.1202","url":null,"abstract":"Developing more specialized care for neurological disorders, such as aneurysms, arteriovenous malformations, and strokes, can revolutionize patient healthcare and outcomes. With the advent of surgical techniques such as flow diversion, non-stent- and stent-assisted coiling, and catheter embolization for elective aneurysm treatment in neurological patients, the adverse effects and morbidities associated with aneurysms can be reduced. This paper aims to highlight three specific strengths and weaknesses of the newly emerged techniques. Flow diversion devices involve placing a stent in the parent artery, whereas Woven EndoBridge embolization involves manipulation of the wall of the artery without the administration of dual-antiplatelet therapy. In addition to aneurysm treatment, the administration of antiplatelets and anticoagulants is helpful in disrupting the coagulation cascade. As stated in the new and enhanced guidelines released by the American Heart Association, the administration of dual anticoagulants is beneficial to the patients if they have low ischemic severity. Understanding the various benefits and complications associated with each treatment can allow clinicians to gain insight into the potential trajectory of treatment for different patients.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"243 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135824072","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}
Spinal cord injury without radiological abnormality (SCIWORA) is a rare condition that predominantly affects children. The enigmatic nature of SCIWORA poses significant challenges in terms of diagnosis, treatment, and achieving full recovery. Various factors, such as different injury mechanisms, delayed symptom onset, normal magnetic resonance imaging findings in certain cases, and complex management decisions, contribute to the challenges of dealing with SCIWORA. Attaining a significant outcome and complete recovery through a single-treatment approach is difficult. Therefore, a multifaceted treatment strategy is proposed to yield more favorable results. This paper comprehensively addresses the assessment and management, examination and diagnosis procedures, treatment methods, rehabilitation techniques, and potential complications associated with SCIWORA in children. The paper provides therapeutic guidance for physicians and medical staff, with the aim of enhancing survival rates and improving recovery outcomes. Moreover, it offers suggestions for restoring neurological functions in pediatric patients suffering from SCIWORA.
{"title":"Guidelines for treating spinal cord injury without radiological abnormalities in children","authors":"Ruba Altahla, Jamal Alshorman, Xu Tao","doi":"10.36922/itps.1386","DOIUrl":"https://doi.org/10.36922/itps.1386","url":null,"abstract":"Spinal cord injury without radiological abnormality (SCIWORA) is a rare condition that predominantly affects children. The enigmatic nature of SCIWORA poses significant challenges in terms of diagnosis, treatment, and achieving full recovery. Various factors, such as different injury mechanisms, delayed symptom onset, normal magnetic resonance imaging findings in certain cases, and complex management decisions, contribute to the challenges of dealing with SCIWORA. Attaining a significant outcome and complete recovery through a single-treatment approach is difficult. Therefore, a multifaceted treatment strategy is proposed to yield more favorable results. This paper comprehensively addresses the assessment and management, examination and diagnosis procedures, treatment methods, rehabilitation techniques, and potential complications associated with SCIWORA in children. The paper provides therapeutic guidance for physicians and medical staff, with the aim of enhancing survival rates and improving recovery outcomes. Moreover, it offers suggestions for restoring neurological functions in pediatric patients suffering from SCIWORA.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"68 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135858944","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}
Helicobacter pylori infection, pepsin, ischemia, hypoxia, smoking, alcohol intake, hydrochloric acid, and nonsteroidal anti-inflammatory drugs are the causal factors of ulceration. In third-world countries, approximately one in two individuals has signs of gastric ulceration. Extensive literature suggested that plant-derived drugs hold the potential in the treatment of peptic ulcer, and Rheum spiciforme (family: Polygonaceae) has been known in the folk medicine for possessing medicinal effect on ulceration. To explore further along this line, the current study was designed to investigate the effects of aqueous ethanol extract of R. spiciforme roots and its fractions on peptic ulcer and to identify bioactive compounds responsible for mitigating this pathological condition. Animal model of ethanol-induced gastric ulcer was utilized in this study. The animals were pre-treated with crude plant extract, given at doses 125, 250, and 500 mg/kg, and then orally administered with butanol, aqueous, and dichloromethane fractions at doses of 250 mg/kg for 7 days. Following the treatments, a significant decrease in ulcerative lesions, ulcer index, ulcer severity score, volume, free acidity, and total acidity of gastric juice as well as a marked increase of gastric pH in the groups treated with plant extract at doses of 250 and 500 mg/kg were noted. Moreover, butanol fraction has been shown to produce effects equipotent to that of the reference drug omeprazole. Liquid chromatography-mass spectrometry analyses show that the plant extract contains emodin, aloe-emodin, and quercetin. In conclusion, this study demonstrated that the aqueous ethanol extract of R. spiciforme and its butanol fraction exhibited gastro-protective effect.
{"title":"Anti-ulcer activity of aqueous ethanol extract of Rheum spiciforme and its fractions in animal model","authors":"Hafiz Muhammad Irfan, Maham Idrees, Kainat Jabeen","doi":"10.36922/itps.1343","DOIUrl":"https://doi.org/10.36922/itps.1343","url":null,"abstract":"Helicobacter pylori infection, pepsin, ischemia, hypoxia, smoking, alcohol intake, hydrochloric acid, and nonsteroidal anti-inflammatory drugs are the causal factors of ulceration. In third-world countries, approximately one in two individuals has signs of gastric ulceration. Extensive literature suggested that plant-derived drugs hold the potential in the treatment of peptic ulcer, and Rheum spiciforme (family: Polygonaceae) has been known in the folk medicine for possessing medicinal effect on ulceration. To explore further along this line, the current study was designed to investigate the effects of aqueous ethanol extract of R. spiciforme roots and its fractions on peptic ulcer and to identify bioactive compounds responsible for mitigating this pathological condition. Animal model of ethanol-induced gastric ulcer was utilized in this study. The animals were pre-treated with crude plant extract, given at doses 125, 250, and 500 mg/kg, and then orally administered with butanol, aqueous, and dichloromethane fractions at doses of 250 mg/kg for 7 days. Following the treatments, a significant decrease in ulcerative lesions, ulcer index, ulcer severity score, volume, free acidity, and total acidity of gastric juice as well as a marked increase of gastric pH in the groups treated with plant extract at doses of 250 and 500 mg/kg were noted. Moreover, butanol fraction has been shown to produce effects equipotent to that of the reference drug omeprazole. Liquid chromatography-mass spectrometry analyses show that the plant extract contains emodin, aloe-emodin, and quercetin. In conclusion, this study demonstrated that the aqueous ethanol extract of R. spiciforme and its butanol fraction exhibited gastro-protective effect.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"76 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135858641","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}
Funmilayo I. D. Afolayan, Deborah G. Joseph, Ridwan A. Salaam
Immunomodulation constitutes a crucial part of individual organisms’ defense systems. Moreover, the utilization of plant-based natural products as herbal medicine for immunomodulation has garnered significant interest. Herein, we examined the immunomodulatory potentials of active phytocompounds extracted from Withania somnifera and Aloe barbadensis by employing ADMET screening, network pharmacology, and molecular docking techniques. This study follows the paradigm in drug discovery, which has shifted from a “one-target, one-drug” mode to a “network-target, multiple-component-therapeutics” mode. Phyto compounds sourced from W. somnifera and A. barbadensis were mined from online databases, including Dr. Duke’s Phytochemical Ethnobotanical Database. After screening these active compounds, their potential targets were predicted through in silico ADMET property prediction models. Network pharmacology was utilized to establish a “compound-protein/gene-disease” network and reveal the regulatory mechanism of small molecules in a high-throughput manner through STRING, Cytohubba plugin in Cytoscape, and the g: Profiler software. A molecular docking simulation was performed to examine the binding affinity between the selected hub targets and bioactives. The findings showed that phytocompounds derived from the W. somnifera and A. barbadensis exhibit immunomodulatory effects by inhibiting specific protein targets, notably AKT1, HCK, JAK2, PDPK1, KIT, and IL2. Molecular docking analysis further revealed the potential of withanolide G, somniferine, and somniferanolide as promising immunomodulatory compounds against HCK, JAK2, and PDPK1 proteins, which are involved in multiple myeloma pathways, encompassing the PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, and Toll-like receptor signaling pathway. In conclusion, these compounds are recommended for further in vivo and in vitro investigations to ascertain their potential as treatments for multiple myeloma.
{"title":"Network pharmacology-based findings of the immunomodulatory activity of phytocompounds from Withania somnifera and Aloe barbadensis","authors":"Funmilayo I. D. Afolayan, Deborah G. Joseph, Ridwan A. Salaam","doi":"10.36922/itps.1076","DOIUrl":"https://doi.org/10.36922/itps.1076","url":null,"abstract":"Immunomodulation constitutes a crucial part of individual organisms’ defense systems. Moreover, the utilization of plant-based natural products as herbal medicine for immunomodulation has garnered significant interest. Herein, we examined the immunomodulatory potentials of active phytocompounds extracted from Withania somnifera and Aloe barbadensis by employing ADMET screening, network pharmacology, and molecular docking techniques. This study follows the paradigm in drug discovery, which has shifted from a “one-target, one-drug” mode to a “network-target, multiple-component-therapeutics” mode. Phyto compounds sourced from W. somnifera and A. barbadensis were mined from online databases, including Dr. Duke’s Phytochemical Ethnobotanical Database. After screening these active compounds, their potential targets were predicted through in silico ADMET property prediction models. Network pharmacology was utilized to establish a “compound-protein/gene-disease” network and reveal the regulatory mechanism of small molecules in a high-throughput manner through STRING, Cytohubba plugin in Cytoscape, and the g: Profiler software. A molecular docking simulation was performed to examine the binding affinity between the selected hub targets and bioactives. The findings showed that phytocompounds derived from the W. somnifera and A. barbadensis exhibit immunomodulatory effects by inhibiting specific protein targets, notably AKT1, HCK, JAK2, PDPK1, KIT, and IL2. Molecular docking analysis further revealed the potential of withanolide G, somniferine, and somniferanolide as promising immunomodulatory compounds against HCK, JAK2, and PDPK1 proteins, which are involved in multiple myeloma pathways, encompassing the PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, and Toll-like receptor signaling pathway. In conclusion, these compounds are recommended for further in vivo and in vitro investigations to ascertain their potential as treatments for multiple myeloma.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"218 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134970200","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}
Godlo Sesethu, Maxam Nombalentle, Mthembu Yamkela, Mpumza Anelisa, Stanley Makumire, Noxolo Mkwetshana, Krishna K. Govender, Xolani H. Makhoba
The current drugs available in the market are not effective due to growing numbers of resistance to the causative agent of malaria. There are various Plasmodium parasites, of which Plasmodium falciparum is the main cause of morbidity and mortality reported worldwide. Therefore, there is an urgent need to come up with an innovative and effective treatment for this disease. Polyamines play a major role in the parasite’s well-being and growth, while heat shock proteins keep the proteomics of the parasite in good shape. In this study, an in silico analysis of the interaction between putrescine, spermidine, spermine, and heat shock proteins was carried out to establish the binding site for drug discovery. Computational tools such as Bioedit, PROCHECK, KNIME Hub, and Schrodinger were used. The results revealed interactions between polyamines and heat shock proteins with glutamine and aspartic acid being common amino acids where interaction occurs between the chaperones and polyamines. Molecular dynamics showed a strong interaction between PfHsp70-1 and putrescine, but the best interaction is observed for PfHsp70-1 and spermidine. Based on these results, a follow-up study will be conducted to establish the synthesis of drugs that will be used as targets for both polyamines and heat shock proteins to eradicate malaria.
{"title":"In silico evaluation of heat shock proteins reveals an interplay with polyamines as a survival strategy for the Plasmodium falciparum","authors":"Godlo Sesethu, Maxam Nombalentle, Mthembu Yamkela, Mpumza Anelisa, Stanley Makumire, Noxolo Mkwetshana, Krishna K. Govender, Xolani H. Makhoba","doi":"10.36922/itps.1228","DOIUrl":"https://doi.org/10.36922/itps.1228","url":null,"abstract":"The current drugs available in the market are not effective due to growing numbers of resistance to the causative agent of malaria. There are various Plasmodium parasites, of which Plasmodium falciparum is the main cause of morbidity and mortality reported worldwide. Therefore, there is an urgent need to come up with an innovative and effective treatment for this disease. Polyamines play a major role in the parasite’s well-being and growth, while heat shock proteins keep the proteomics of the parasite in good shape. In this study, an in silico analysis of the interaction between putrescine, spermidine, spermine, and heat shock proteins was carried out to establish the binding site for drug discovery. Computational tools such as Bioedit, PROCHECK, KNIME Hub, and Schrodinger were used. The results revealed interactions between polyamines and heat shock proteins with glutamine and aspartic acid being common amino acids where interaction occurs between the chaperones and polyamines. Molecular dynamics showed a strong interaction between PfHsp70-1 and putrescine, but the best interaction is observed for PfHsp70-1 and spermidine. Based on these results, a follow-up study will be conducted to establish the synthesis of drugs that will be used as targets for both polyamines and heat shock proteins to eradicate malaria.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135688905","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}
Oluwafemi S. Aina, Luqman A. Adams, Adebayo J. Bello, Oluwole B. Familoni
Aspartic proteases can hydrolyze peptide bonds, making them potential targets for drug development against malaria parasites. In particular, inhibiting the histoaspartic protease (HAP) can disrupt the growth phase of Plasmodium falciparum and its ability to degrade hemoglobin for protein synthesis. Compound 5, specifically designed as 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde, served as the basis for designing 50 hypothetical compounds (A1-A50). These compounds were subjected to in silico screening to assess their toxicity profiles, pharmacokinetics, bioactivity scores, and theoretical binding affinities, as a part of the drug design protocol. Out of the 50 compounds, nine lead candidates showed no toxicity to human cells. In addition, ten standard reference antimalarial drugs were included in this study for comparison. The highest binding energies were observed for compound A5 (−11.2 kcal/mol) and A31 (−11.3 kcal/mol), surpassing the performance of mefloquine, the best reference drug, which ranked ninth with a binding energy of (−9.6 kcal/mol). Compound A31 did not exhibit the evidence of interaction with either Asp215 or His32, whereas compound A5 displayed π-π stacking interactions with His32. Mefloquine also did not show any interaction with Asp215 or His32. Moreover, compound A5 demonstrated greater hydrophobic interactions at the active site with most binding residues, except for Lys7 in the hydrophobic region. This characteristic suggests that compound A5 may have the ability to adopt a smaller surface area, exhibit increased biological activity, and have reduced interactions with water, which could facilitate slower clearance. Based on the assessment of various drug-likeness parameters, compound A5 (2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde) is a potential lead candidate for the development of a new antimalarial drug.
{"title":"Plasmodium falciparum histoaspartic protease inhibitor: Toxicity investigation and docking study of 2-(2-benzoyl-4-methylphenoxy) quinoline-3-carbaldehyde derivatives","authors":"Oluwafemi S. Aina, Luqman A. Adams, Adebayo J. Bello, Oluwole B. Familoni","doi":"10.36922/itps.0976","DOIUrl":"https://doi.org/10.36922/itps.0976","url":null,"abstract":"Aspartic proteases can hydrolyze peptide bonds, making them potential targets for drug development against malaria parasites. In particular, inhibiting the histoaspartic protease (HAP) can disrupt the growth phase of Plasmodium falciparum and its ability to degrade hemoglobin for protein synthesis. Compound 5, specifically designed as 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde, served as the basis for designing 50 hypothetical compounds (A1-A50). These compounds were subjected to in silico screening to assess their toxicity profiles, pharmacokinetics, bioactivity scores, and theoretical binding affinities, as a part of the drug design protocol. Out of the 50 compounds, nine lead candidates showed no toxicity to human cells. In addition, ten standard reference antimalarial drugs were included in this study for comparison. The highest binding energies were observed for compound A5 (−11.2 kcal/mol) and A31 (−11.3 kcal/mol), surpassing the performance of mefloquine, the best reference drug, which ranked ninth with a binding energy of (−9.6 kcal/mol). Compound A31 did not exhibit the evidence of interaction with either Asp215 or His32, whereas compound A5 displayed π-π stacking interactions with His32. Mefloquine also did not show any interaction with Asp215 or His32. Moreover, compound A5 demonstrated greater hydrophobic interactions at the active site with most binding residues, except for Lys7 in the hydrophobic region. This characteristic suggests that compound A5 may have the ability to adopt a smaller surface area, exhibit increased biological activity, and have reduced interactions with water, which could facilitate slower clearance. Based on the assessment of various drug-likeness parameters, compound A5 (2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde) is a potential lead candidate for the development of a new antimalarial drug.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"37 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135688906","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}
The main difficulty in the treatment of cancer lies in the already known mechanism of resistance to conventional chemotherapy. It is mainly due to the expression of the multidrug transport systems known as ABC transporters, both in neoplastic cells and in excretory organs that reduce the chemotherapeutic concentration. The cancer cell proliferation by activation of growth factor receptors induces their intrinsic tyrosine kinase activity, and their intracellular signaling pathways involved in such activation. Tumor proliferation can respond to the direct action of growth factors on their respective receptors, or due to somatic mutations in different steps of their signaling pathway, in an independent manner of growth factor stimulus. Pharmacogenetics studies have been performed to identify these drivers’ mutations and their detection enables targeted inhibitory therapies against their abnormal proteins. The design of new molecules capable of inhibiting these signals has opened a new line of treatment for each type of tumor, thereby enabling tumor growth control and giving rise to the precision medicine approach. It is possible that mutations of sensitive and resistant to these targeted therapies coexist in the same tumor, from the start of therapy or as a consequence of the first-line treatment. The mutations in circulating DNA in body fluids, which are detected and quantified by droplet digital polymerase chain reaction-assisted liquid biopsy, are the ideal biomarkers for the evaluation of pharmacological response, which is crucial for facilitating the change of therapeutic strategy involving second- or third-generation drugs. The quantification of these mutations can be used to assess minimal residual disease in the therapeutic follow-up of each case.
{"title":"Pharmacogenetic and liquid biopsy: The new tools of precision medicine in cancer","authors":"Verónica Alejandra Alonso, Alberto Lazarowski","doi":"10.36922/itps.1227","DOIUrl":"https://doi.org/10.36922/itps.1227","url":null,"abstract":"The main difficulty in the treatment of cancer lies in the already known mechanism of resistance to conventional chemotherapy. It is mainly due to the expression of the multidrug transport systems known as ABC transporters, both in neoplastic cells and in excretory organs that reduce the chemotherapeutic concentration. The cancer cell proliferation by activation of growth factor receptors induces their intrinsic tyrosine kinase activity, and their intracellular signaling pathways involved in such activation. Tumor proliferation can respond to the direct action of growth factors on their respective receptors, or due to somatic mutations in different steps of their signaling pathway, in an independent manner of growth factor stimulus. Pharmacogenetics studies have been performed to identify these drivers’ mutations and their detection enables targeted inhibitory therapies against their abnormal proteins. The design of new molecules capable of inhibiting these signals has opened a new line of treatment for each type of tumor, thereby enabling tumor growth control and giving rise to the precision medicine approach. It is possible that mutations of sensitive and resistant to these targeted therapies coexist in the same tumor, from the start of therapy or as a consequence of the first-line treatment. The mutations in circulating DNA in body fluids, which are detected and quantified by droplet digital polymerase chain reaction-assisted liquid biopsy, are the ideal biomarkers for the evaluation of pharmacological response, which is crucial for facilitating the change of therapeutic strategy involving second- or third-generation drugs. The quantification of these mutations can be used to assess minimal residual disease in the therapeutic follow-up of each case.","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135981514","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}
Pub Date : 2023-01-01Epub Date: 2023-08-03DOI: 10.36922/itps.417
Drashti Patel, Andrew Nguyen, Chance Fleeting, Anjali B Patel, Mohammed Mumtaz, Brandon Lucke-Wold
Theranostics in neurosurgery is a rapidly advancing field of precision medicine that combines diagnostic and therapeutic modalities to optimize patient outcomes. This approach has the potential to provide real-time feedback during therapy and diagnose a condition while simultaneously providing treatment. One such form of theranostics is focused ultrasound, which has been found to be effective in inducing neuroablation and neuromodulation and improving the efficacy of chemotherapy drugs by disrupting the blood-brain barrier. Targeted radionuclide therapy, which pairs positron emission tomography tracers with therapeutic effects and imaging modalities, is another promising form of theranostics for neurosurgery. Automated pathology analysis is yet another form of theranostics that can provide real-time feedback during the surgical resection of tumors. Electrical stimulation has also shown promise in optimizing therapies for patients with cerebral palsy. Overall, theranostics is a cost-effective way to optimize medical care for patients in neurosurgery. It is a relatively new field, but the advancements made so far show great promise for improving patient outcomes.
{"title":"Precision medicine in neurosurgery: The evolving role of theranostics.","authors":"Drashti Patel, Andrew Nguyen, Chance Fleeting, Anjali B Patel, Mohammed Mumtaz, Brandon Lucke-Wold","doi":"10.36922/itps.417","DOIUrl":"10.36922/itps.417","url":null,"abstract":"<p><p>Theranostics in neurosurgery is a rapidly advancing field of precision medicine that combines diagnostic and therapeutic modalities to optimize patient outcomes. This approach has the potential to provide real-time feedback during therapy and diagnose a condition while simultaneously providing treatment. One such form of theranostics is focused ultrasound, which has been found to be effective in inducing neuroablation and neuromodulation and improving the efficacy of chemotherapy drugs by disrupting the blood-brain barrier. Targeted radionuclide therapy, which pairs positron emission tomography tracers with therapeutic effects and imaging modalities, is another promising form of theranostics for neurosurgery. Automated pathology analysis is yet another form of theranostics that can provide real-time feedback during the surgical resection of tumors. Electrical stimulation has also shown promise in optimizing therapies for patients with cerebral palsy. Overall, theranostics is a cost-effective way to optimize medical care for patients in neurosurgery. It is a relatively new field, but the advancements made so far show great promise for improving patient outcomes.</p>","PeriodicalId":73386,"journal":{"name":"INNOSC theranostics & pharmacological sciences","volume":"6 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10424317","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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