Pub Date : 2024-10-01Epub Date: 2023-08-29DOI: 10.1080/07391102.2023.2249115
Akanksha Dubey, Jayanthi Sivaraman
Inflammation is the preliminary response given to any possible harmful stimuli including infections, injury or stress by immune system where neutrophils and macrophages gets activated and produces mediators, such as nitric oxide and cytokines that serves as biomarkers of inflammation. Lipoxygenases are enzymes that peroxidises lipids and are involved in the pathogenesis of several diseases including inflammatory diseases. These are oxidative enzymes comprising a non-heme iron atom in active site and are convoluted in inflammatory reactions. Fucoidan is sulphated polysaccharide that has numerous pharmacological implications. Implications of fucoidan on inflammatory diseases are still an objective of rigorous research. Therefore, this study focusses on investigating lipoxygenase inhibitory activities of fucoidan. The mechanism of lipoxygenase inhibitory activities of fucoidan was studied via molecular docking and molecular dynamics simulations. The docking score produced by the binding of the fucoidan to the lipoxygenase was - 6.69 kcal/mol whereas, the docking score in case of Aspirin and Zileuton were -5.8 kcal/mol and -7.0 kcal/mol and it was found that fucoidan makes hydrogen bonds with lipoxygenase protein through polar amino acid glutamine at GLN 514. The results obtained from molecular dynamics simulations proposed the development of a stable complex between fucoidan and lipoxygenase due to the establishment of favourable interactions with amino acid residues and indicated efficient results when compared with Aspirin and Zileuton. This study suggested that fucoidan had anti-inflammatory potentials and thus can be used as a promising drug candidate against inflammation.Communicated by Ramaswamy H. Sarma.
{"title":"Investigating anti-inflammatory actions of marine algal compound against lipoxygenase concentrating on therapeutic applications through computational approach.","authors":"Akanksha Dubey, Jayanthi Sivaraman","doi":"10.1080/07391102.2023.2249115","DOIUrl":"10.1080/07391102.2023.2249115","url":null,"abstract":"<p><p>Inflammation is the preliminary response given to any possible harmful stimuli including infections, injury or stress by immune system where neutrophils and macrophages gets activated and produces mediators, such as nitric oxide and cytokines that serves as biomarkers of inflammation. Lipoxygenases are enzymes that peroxidises lipids and are involved in the pathogenesis of several diseases including inflammatory diseases. These are oxidative enzymes comprising a non-heme iron atom in active site and are convoluted in inflammatory reactions. Fucoidan is sulphated polysaccharide that has numerous pharmacological implications. Implications of fucoidan on inflammatory diseases are still an objective of rigorous research. Therefore, this study focusses on investigating lipoxygenase inhibitory activities of fucoidan. The mechanism of lipoxygenase inhibitory activities of fucoidan was studied <i>via</i> molecular docking and molecular dynamics simulations. The docking score produced by the binding of the fucoidan to the lipoxygenase was - 6.69 kcal/mol whereas, the docking score in case of Aspirin and Zileuton were -5.8 kcal/mol and -7.0 kcal/mol and it was found that fucoidan makes hydrogen bonds with lipoxygenase protein through polar amino acid glutamine at GLN 514. The results obtained from molecular dynamics simulations proposed the development of a stable complex between fucoidan and lipoxygenase due to the establishment of favourable interactions with amino acid residues and indicated efficient results when compared with Aspirin and Zileuton. This study suggested that fucoidan had anti-inflammatory potentials and thus can be used as a promising drug candidate against inflammation.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10467730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-08-22DOI: 10.1080/07391102.2023.2249101
Olanrewaju Ayodeji Durojaye
Phosphorylation is the most prevalent form of regulation in cells, organizing virtually all cellular functions, including survival, motility, differentiation, proliferation, and metabolism. This regulatory function has been largely conserved from the primitive single-cell to the more complex multicellular organisms. More than a third of proteins in eukaryotes are phosphorylated, and essentially every class of protein undergoes regulation by phosphorylation. A decline in the cellular level of CENP-L and CENP-N (components of the constitutive centromere associated network) has earlier been reported and linked to cyclin-dependent kinase (CDK) phosphorylation upon transition into mitosis. Given the importance of posttranslational modifications in cell cycle regulation, mechanistic comprehension of the impact of phosphorylation on both proteins (CENP-L and CENP-N) is of high significance. Through the application of diverse computational analytical techniques, including atomistic molecular dynamics simulations, the mechanism of kinetochore mis-localization and dissociation of the CENP-LN sub-complex in mitosis was delineated. We showed that the phosphorylation of both components of the sub-complex induces global conformational destabilizing effects on the proteins, combined with changes in the electrostatic potential and increase in steric clashes around the protein-protein interaction interface. This, consistent with earlier experimental reports, suggest that the multisite phosphorylation of the CENP-LN sub-complex plays a crucial role in the regulation of cell division.Communicated by Ramaswamy H. Sarma.
{"title":"Delineation of the CENP-LN sub-complex dissociation mechanism upon multisite phosphorylation during mitosis.","authors":"Olanrewaju Ayodeji Durojaye","doi":"10.1080/07391102.2023.2249101","DOIUrl":"10.1080/07391102.2023.2249101","url":null,"abstract":"<p><p>Phosphorylation is the most prevalent form of regulation in cells, organizing virtually all cellular functions, including survival, motility, differentiation, proliferation, and metabolism. This regulatory function has been largely conserved from the primitive single-cell to the more complex multicellular organisms. More than a third of proteins in eukaryotes are phosphorylated, and essentially every class of protein undergoes regulation by phosphorylation. A decline in the cellular level of CENP-L and CENP-N (components of the constitutive centromere associated network) has earlier been reported and linked to cyclin-dependent kinase (CDK) phosphorylation upon transition into mitosis. Given the importance of posttranslational modifications in cell cycle regulation, mechanistic comprehension of the impact of phosphorylation on both proteins (CENP-L and CENP-N) is of high significance. Through the application of diverse computational analytical techniques, including atomistic molecular dynamics simulations, the mechanism of kinetochore mis-localization and dissociation of the CENP-LN sub-complex in mitosis was delineated. We showed that the phosphorylation of both components of the sub-complex induces global conformational destabilizing effects on the proteins, combined with changes in the electrostatic potential and increase in steric clashes around the protein-protein interaction interface. This, consistent with earlier experimental reports, suggest that the multisite phosphorylation of the CENP-LN sub-complex plays a crucial role in the regulation of cell division.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10040511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-08-25DOI: 10.1080/07391102.2023.2250452
Esmail M El-Fakharany, Hamada El-Gendi, Khaled Abdel-Wahhab, Marwa M Abu-Serie, Doaa Galal El-Sahra, Mahmoud Ashry
Colorectal cancer (CRC) is a malignant tumor recognized as a major cause of morbidity and mortality throughout the world. Therefore, novel liposomes of oleic acid coated with camel α-lactalbumin (α-LA coated liposomes) were developed for their potential antitumor activity against CRC, both in vitro and in DMH-induced CRC-modeled animal. In vitro results indicated the high safety of α-LA coated liposomes towards normal human cells with potent antitumor activity against Caco-2 cells at an IC50 value of 57.01 ± 3.55 µM with selectivity index of 6.92 ± 0.48. This antitumor activity has been attributed to induction of the apoptotic mechanism, as demonstrated by nuclear condensation and arrest of Caco-2 cells in sub-G1 populations. α-LA coated liposomes also revealed a significant up-regulation of the p53 gene combined with a down-regulation of the Bcl2 gene. Moreover, in vivo results revealed that treatment of induced-CRC modeled animals with α-LA coated liposomes for six weeks markedly improved the CRC-disorders; this was achieved from the significant reduction in the values of AFP, CEA, CA19.9, TNF-α, IL-1β, MDA, and NO coupled with remarkable rise in SOD, GPx, GSH, CAT, and CD4+ levels. The histopathological findings asserted the therapeutic potential of α-LA coated liposomes in the treatment of CRC. Therefore, the present results proved the antitumor activity of α-LA coated liposomes against CRC through the restoration of impaired oxidative stress, improved immune response, and reduced inflammation.Communicated by Ramaswamy H. Sarma.
{"title":"Therapeutic efficacy of α-lactalbumin coated oleic acid based liposomes against colorectal carcinoma in Caco-2 cells and DMH-treated albino rats.","authors":"Esmail M El-Fakharany, Hamada El-Gendi, Khaled Abdel-Wahhab, Marwa M Abu-Serie, Doaa Galal El-Sahra, Mahmoud Ashry","doi":"10.1080/07391102.2023.2250452","DOIUrl":"10.1080/07391102.2023.2250452","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a malignant tumor recognized as a major cause of morbidity and mortality throughout the world. Therefore, novel liposomes of oleic acid coated with camel α-lactalbumin (α-LA coated liposomes) were developed for their potential antitumor activity against CRC, both <i>in vitro</i> and in DMH-induced CRC-modeled animal. <i>In vitro</i> results indicated the high safety of α-LA coated liposomes towards normal human cells with potent antitumor activity against Caco-2 cells at an IC<sub>50</sub> value of 57.01 ± 3.55 µM with selectivity index of 6.92 ± 0.48. This antitumor activity has been attributed to induction of the apoptotic mechanism, as demonstrated by nuclear condensation and arrest of Caco-2 cells in sub-G1 populations. α-LA coated liposomes also revealed a significant up-regulation of the p53 gene combined with a down-regulation of the Bcl2 gene. Moreover, <i>in vivo</i> results revealed that treatment of induced-CRC modeled animals with α-LA coated liposomes for six weeks markedly improved the CRC-disorders; this was achieved from the significant reduction in the values of AFP, CEA, CA19.9, TNF-α, IL-1β, MDA, and NO coupled with remarkable rise in SOD, GPx, GSH, CAT, and CD4+ levels. The histopathological findings asserted the therapeutic potential of α-LA coated liposomes in the treatment of CRC. Therefore, the present results proved the antitumor activity of α-LA coated liposomes against CRC through the restoration of impaired oxidative stress, improved immune response, and reduced inflammation.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10069777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-08-24DOI: 10.1080/07391102.2023.2250479
Ibrahim M Ibrahim, Abdo A Elfiky, Sara H Mahmoud, Mahmoud ElHefnawi
Researchers worldwide are looking for molecules that might disrupt the COVID-19 life cycle. Endoribonuclease, which is responsible for processing viral RNA to avoid detection by the host defense system, and helicase, which is responsible for unwinding the RNA helices for replication, are two key non-structural proteins. This study performs a hierarchical structure-based virtual screening approach for NSP15 and helicase to reach compounds with high binding probabilities. In this investigation, we incorporated a variety of filtering strategies for predicting compound interactions. First, we evaluated 756,275 chemicals from four databases using a deep learning method (NCI, Drug Bank, Maybridge, and COCONUT). Following that, two docking techniques (extra precision and induced fit) were utilized to evaluate the compounds' binding affinity, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy calculation. Remarkably, two compounds (90616 and CNP0111740) exhibited high binding affinity values of -66.03 and -12.34 kcal/mol for helicase and NSP15, respectively. The VERO-E6 cell line was employed to test their in vitro therapeutic impact. The CC50 for CNP0111740 and 90616 were determined to be 102.767 μg/ml and 379.526 μg/ml, while the IC50 values were 140.176 μg/ml and 5.147 μg/ml, respectively. As a result, the selectivity index for CNP0111740 and 90616 is 0.73 and 73.73, respectively. Finally, these compounds were found to be novel, effective inhibitors for the virus; however, further in vivo validation is needed.Communicated by Ramaswamy H. Sarma.
{"title":"A structural-based virtual screening and <i>in vitro</i> validation reveals novel effective inhibitors for SARS-CoV-2 helicase and endoribonuclease.","authors":"Ibrahim M Ibrahim, Abdo A Elfiky, Sara H Mahmoud, Mahmoud ElHefnawi","doi":"10.1080/07391102.2023.2250479","DOIUrl":"10.1080/07391102.2023.2250479","url":null,"abstract":"<p><p>Researchers worldwide are looking for molecules that might disrupt the COVID-19 life cycle. Endoribonuclease, which is responsible for processing viral RNA to avoid detection by the host defense system, and helicase, which is responsible for unwinding the RNA helices for replication, are two key non-structural proteins. This study performs a hierarchical structure-based virtual screening approach for NSP15 and helicase to reach compounds with high binding probabilities. In this investigation, we incorporated a variety of filtering strategies for predicting compound interactions. First, we evaluated 756,275 chemicals from four databases using a deep learning method (NCI, Drug Bank, Maybridge, and COCONUT). Following that, two docking techniques (extra precision and induced fit) were utilized to evaluate the compounds' binding affinity, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy calculation. Remarkably, two compounds (90616 and CNP0111740) exhibited high binding affinity values of -66.03 and -12.34 kcal/mol for helicase and NSP15, respectively. The VERO-E6 cell line was employed to test their <i>in vitro</i> therapeutic impact. The CC<sub>50</sub> for CNP0111740 and 90616 were determined to be 102.767 μg/ml and 379.526 μg/ml, while the IC<sub>50</sub> values were 140.176 μg/ml and 5.147 μg/ml, respectively. As a result, the selectivity index for CNP0111740 and 90616 is 0.73 and 73.73, respectively. Finally, these compounds were found to be novel, effective inhibitors for the virus; however, further <i>in vivo</i> validation is needed.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10416040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
DNA topoisomerase I (Topo I) is a ubiquitous enzyme that plays a crucial role in resolving the topological constraints of supercoiled DNA during various cellular activities, including repair, replication, recombination, transcription, and chromatin remodeling. Multiple studies have confirmed the essential role of Topo I in nucleic acid metabolism of Leishmania donovani, the kinetoplastid parasite responsible for visceral leishmaniasis or kala-azar. Inhibition of this enzyme has shown promise as a strategy for therapy against visceral leishmaniasis. However, current treatment options suffer from limitations related to effectiveness, cost, and side effects. To address these challenges, computational methods have been employed in this study to investigate the inhibition of Leishmania donovani DNA topoisomerase I (LdTopo I) by phytochemicals derived from Indian medicinal plants known for their anti-leishmanial activity. A library of phytochemicals and known inhibitors was assembled, and virtual screening based on docking binding affinities was conducted to identify potent phytochemical inhibitors. To assess the drug-likeness of the docked phytochemicals, their physicochemical properties were predicted. Additionally, molecular dynamics (MD) simulations were performed on the docked complexes for a duration of 100 ns to evaluate their stability, intermolecular interactions, and dynamic behavior. Among all the docked phytochemicals, three compounds, namely CID23266147 (withanolide N), CID5488537 (fagopyrine), and CID100947536 (isozeylanone), exhibited the highest inhibitory potential against LdTopo I. These findings hold promise for the development of novel inhibitors targeting LdTopo I, which could potentially lead to improved therapies for visceral leishmaniasis.Communicated by Ramaswamy H. Sarma.
DNA 拓扑异构酶 I(Topo I)是一种无处不在的酶,在修复、复制、重组、转录和染色质重塑等各种细胞活动中,它在解决超螺旋 DNA 的拓扑限制方面发挥着至关重要的作用。多项研究证实,Topo I 在多诺万利什曼病(Leishmania donovani)的核酸代谢中起着至关重要的作用。抑制这种酶有望成为治疗内脏利什曼病的一种策略。然而,目前的治疗方案在有效性、成本和副作用方面存在局限性。为了应对这些挑战,本研究采用了计算方法来研究印度药用植物中以抗利什曼病活性著称的植物化学物质对多诺万利什曼病DNA拓扑异构酶I(LdTopo I)的抑制作用。我们建立了一个植物化学物质和已知抑制剂库,并根据对接结合亲和力进行了虚拟筛选,以确定有效的植物化学抑制剂。为了评估对接植物化学物的药物相似性,对其理化性质进行了预测。此外,还对对接复合物进行了持续 100 ns 的分子动力学(MD)模拟,以评估其稳定性、分子间相互作用和动态行为。在所有对接的植物化学物质中,CID23266147(withanolide N)、CID5488537(fagopyrine)和 CID100947536(isozeylanone)这三种化合物对 LdTopo I 的抑制潜力最高。这些发现为开发针对 LdTopo I 的新型抑制剂带来了希望,从而有可能改进内脏利什曼病的疗法。
{"title":"Computational evaluation of phytochemicals targeting DNA topoisomerase I in <i>Leishmania donovani</i>: molecular docking and molecular dynamics simulation studies.","authors":"Praffulla Kumar Arya, Pranabesh Mandal, Krishnendu Barik, Durg Vijay Singh, Anil Kumar","doi":"10.1080/07391102.2023.2256865","DOIUrl":"10.1080/07391102.2023.2256865","url":null,"abstract":"<p><p>DNA topoisomerase I (Topo I) is a ubiquitous enzyme that plays a crucial role in resolving the topological constraints of supercoiled DNA during various cellular activities, including repair, replication, recombination, transcription, and chromatin remodeling. Multiple studies have confirmed the essential role of Topo I in nucleic acid metabolism of <i>Leishmania donovani</i>, the kinetoplastid parasite responsible for visceral leishmaniasis or kala-azar. Inhibition of this enzyme has shown promise as a strategy for therapy against visceral leishmaniasis. However, current treatment options suffer from limitations related to effectiveness, cost, and side effects. To address these challenges, computational methods have been employed in this study to investigate the inhibition of <i>Leishmania donovani</i> DNA topoisomerase I (LdTopo I) by phytochemicals derived from Indian medicinal plants known for their anti-leishmanial activity. A library of phytochemicals and known inhibitors was assembled, and virtual screening based on docking binding affinities was conducted to identify potent phytochemical inhibitors. To assess the drug-likeness of the docked phytochemicals, their physicochemical properties were predicted. Additionally, molecular dynamics (MD) simulations were performed on the docked complexes for a duration of 100 ns to evaluate their stability, intermolecular interactions, and dynamic behavior. Among all the docked phytochemicals, three compounds, namely CID23266147 (withanolide N), CID5488537 (fagopyrine), and CID100947536 (isozeylanone), exhibited the highest inhibitory potential against LdTopo I. These findings hold promise for the development of novel inhibitors targeting LdTopo I, which could potentially lead to improved therapies for visceral leishmaniasis.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10268316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this paper, we performed thorough experimental and theoretical calculations to examine the interaction between Pt derivative, as an anticancer, and ct-DNA. The mode of DNA binding with [Pt(NH3)2(Isopentylgly)]NO3, where Isopentylgly is Isopentyl glycine, was evaluated by various spectroscopic methods, docking, and molecular dynamics simulation studies. UV-Vis and fluorescence spectroscopic titration results and CD spectra of DNA-drug showed this interaction is via groove binding. Also, thermal stability studies or DNA melting temperature changes (ΔTm), as well as the quenching emissions monitoring proved it. Also, the thermodynamic parameter and binding constant displayed that complex-DNA formation is a spontaneous process, and H-binding and also groove binding were found to be the main forces. Theoretical studies stated [Pt(NH3)2(Isopentylgly)]NO3-DNA formation occurs on C-G center on DNA, along with rising DNA-compound stability. IC50 value against the human breast cell line probably is due to the Isopentyl glycine ligand in the structure of the Pt compound, and it was obtained more than cisplatin and less than carboplatin against the MCF7 cell.Communicated by Ramaswamy H. Sarma.
在本文中,我们进行了深入的实验和理论计算,以研究作为抗癌剂的铂衍生物与ct-DNA之间的相互作用。通过各种光谱方法、对接和分子动力学模拟研究,评估了 DNA 与 [Pt(NH3)2(Isopentylgly)]NO3(其中 Isopentylgly 是异戊基甘氨酸)的结合模式。DNA 与药物的紫外可见光谱、荧光光谱滴定结果和 CD 光谱显示,这种相互作用是通过沟结合进行的。此外,热稳定性研究或 DNA 熔化温度变化(ΔTm)以及淬灭发射监测也证明了这一点。此外,热力学参数和结合常数表明,络合物-DNA 的形成是一个自发过程,H 结合和沟结合是主要作用力。理论研究表明,[Pt(NH3)2(Isopentylgly)]NO3-DNA 的形成发生在 DNA 的 C-G 中心,DNA-化合物的稳定性也随之提高。对人类乳腺细胞系的 IC50 值可能是由于铂化合物结构中的异戊基甘氨酸配体,对 MCF7 细胞的 IC50 值高于顺铂,低于卡铂。
{"title":"Platinum (II) complex of isopentyl glycine ligand: DNA binding, molecular dynamic, and anticancer activity against breast cancer.","authors":"Mahboube Eslami Moghadam, Khadijeh Tavakoli Hafshajani, Nasrin Sohrabi, Morteza Rezaeisadat, Mohsen Oftadeh","doi":"10.1080/07391102.2023.2246564","DOIUrl":"10.1080/07391102.2023.2246564","url":null,"abstract":"<p><p>In this paper, we performed thorough experimental and theoretical calculations to examine the interaction between Pt derivative, as an anticancer, and ct-DNA. The mode of DNA binding with [Pt(NH<sub>3</sub>)<sub>2</sub>(Isopentylgly)]NO<sub>3</sub>, where Isopentylgly is Isopentyl glycine, was evaluated by various spectroscopic methods, docking, and molecular dynamics simulation studies. UV-Vis and fluorescence spectroscopic titration results and CD spectra of DNA-drug showed this interaction is <i>via</i> groove binding. Also, thermal stability studies or DNA melting temperature changes (ΔT<sub>m</sub>), as well as the quenching emissions monitoring proved it. Also, the thermodynamic parameter and binding constant displayed that complex-DNA formation is a spontaneous process, and H-binding and also groove binding were found to be the main forces. Theoretical studies stated [Pt(NH<sub>3</sub>)<sub>2</sub>(Isopentylgly)]NO<sub>3</sub>-DNA formation occurs on C-G center on DNA, along with rising DNA-compound stability. <i>IC<sub>50</sub></i> value against the human breast cell line probably is due to the Isopentyl glycine ligand in the structure of the Pt compound, and it was obtained more than cisplatin and less than carboplatin against the MCF7 cell.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10343661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-08-20DOI: 10.1080/07391102.2023.2248260
Saad Alghamdi, Hanadi M Baeissa, Mohammad Azhar Kamal, Misbahuddin M Rafeeq, Abdullah Al Zahrani, Ali Ahmed Maslum, Israa J Hakeem, Reem S Alazragi, Qamre Alam
Cervical Cancer (CC) is one of the most common types of cancer in women worldwide, with a significant number of deaths reported yearly. Despite the various treatment options available, the high mortality rate associated with CC highlights the need to develop new and effective therapeutic agents. In this study, we have screened the complete prepared FDA library against the Mitotic kinesin-like protein 1, Cyclin B1, DNA polymerase, and MCM10-ID using three glide-based molecular docking algorithms: HTVS, SP and XP to produce a robust calculation. All four proteins are crucial proteins that actively participate in CC development, and inhibiting them together can be a game-changer step for multitargeted drug designing. Our multitargeted screening identified Sodium (Na) Danshensu, a natural FDA-approved phenolic compound of caffeic acid derivatives isolated from Salvia miltiorrhiza. The docking score ranges from -5.892 to -13.103 Kcal/mol, and the screening study was evaluated with the pharmacokinetics and interaction fingerprinting to identify the pattern of interactions that revealed that the compound has bound to the best site it can be fitted to where maximum bonds were created to make the complex stable. The molecular dynamics simulations for 100 ns were then extended to validate the stability of the protein-ligand complexes. The results provide insight into the repurposing, and Na-danshensu exhibited strong binding affinity and stable complex formation with the target proteins, indicating its potential as a multitargeted drug against CC.Communicated by Ramaswamy H. Sarma.
宫颈癌(CC)是全球妇女最常见的癌症类型之一,每年都有大量妇女死亡。尽管有多种治疗方案,但与宫颈癌相关的高死亡率凸显了开发新型有效治疗药物的必要性。在这项研究中,我们利用 HTVS、SP 和 XP 三种基于滑行的分子对接算法,针对有丝分裂驱动蛋白样蛋白 1、细胞周期蛋白 B1、DNA 聚合酶和 MCM10-ID 筛选了完整的 FDA 文库,得出了可靠的计算结果。这四种蛋白都是积极参与CC发育的关键蛋白,同时抑制这四种蛋白可以改变多靶点药物的设计。我们的多靶点筛选确定了丹参素钠(Na),这是一种从丹参中分离出来的天然酚类化合物,含有咖啡酸衍生物,已获美国食品药物管理局批准。对接得分范围为 -5.892 至 -13.103 Kcal/mol,筛选研究结合药代动力学和相互作用指纹图谱进行了评估,以确定相互作用模式,发现该化合物已结合到其所能配合的最佳位点上,在该位点上产生的最大键使复合物稳定。然后将分子动力学模拟时间延长 100 毫微秒,以验证蛋白质配体复合物的稳定性。结果为再利用提供了见解,Na-danshensu与靶蛋白表现出很强的结合亲和力并形成稳定的复合物,这表明它具有作为抗CC多靶点药物的潜力。
{"title":"Unveiling the multitargeted potency of Sodium Danshensu against cervical cancer: a multitargeted docking-based, structural fingerprinting and molecular dynamics simulation study.","authors":"Saad Alghamdi, Hanadi M Baeissa, Mohammad Azhar Kamal, Misbahuddin M Rafeeq, Abdullah Al Zahrani, Ali Ahmed Maslum, Israa J Hakeem, Reem S Alazragi, Qamre Alam","doi":"10.1080/07391102.2023.2248260","DOIUrl":"10.1080/07391102.2023.2248260","url":null,"abstract":"<p><p>Cervical Cancer (CC) is one of the most common types of cancer in women worldwide, with a significant number of deaths reported yearly. Despite the various treatment options available, the high mortality rate associated with CC highlights the need to develop new and effective therapeutic agents. In this study, we have screened the complete prepared FDA library against the Mitotic kinesin-like protein 1, Cyclin B1, DNA polymerase, and MCM10-ID using three glide-based molecular docking algorithms: HTVS, SP and XP to produce a robust calculation. All four proteins are crucial proteins that actively participate in CC development, and inhibiting them together can be a game-changer step for multitargeted drug designing. Our multitargeted screening identified Sodium (Na) Danshensu, a natural FDA-approved phenolic compound of caffeic acid derivatives isolated from <i>Salvia miltiorrhiza</i>. The docking score ranges from -5.892 to -13.103 Kcal/mol, and the screening study was evaluated with the pharmacokinetics and interaction fingerprinting to identify the pattern of interactions that revealed that the compound has bound to the best site it can be fitted to where maximum bonds were created to make the complex stable. The molecular dynamics simulations for 100 ns were then extended to validate the stability of the protein-ligand complexes. The results provide insight into the repurposing, and Na-danshensu exhibited strong binding affinity and stable complex formation with the target proteins, indicating its potential as a multitargeted drug against CC.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10022433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-08-17DOI: 10.1080/07391102.2023.2247087
Asaf Evrim Evren, Demokrat Nuha, Sam Dawbaa, Abdullah Burak Karaduman, Begüm Nurpelin Sağlik, Leyla Yurttaş
In the search for new anticancer agents, we synthesized a new series of thiazole derivatives carried on thiadiazole-oxadiazole hybrid. Final compounds (5a-5i) were analyzed via1H NMR, 13C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted via in silico calculations. Their anticancer properties were determined using MTT method against MCF7 and A549 cell lines. Compounds 5a, 5b and 5c were found more active against MCF7 cells than A549 cells while they were not cytotoxic on L929 healthy cells. Generally, it can be summarized that acetamide moiety has a pivotal role in anticancer activity. For further studies, their aromatase inhibitory activity was evaluated. After determination all these features, the binding modes of the active compounds and the stability and relation of the ligand-enzyme complex were investigated using molecular docking and molecular dynamics simulation studies, respectively. In vitro and in silico studies suggest two important structure-activity relationship (SAR) points that at least one azole ring is essential, and if there is approximately 8.0 ± 0.5 Å distance between the H-bond rich zone of ligand and the heteroaryl ring system of ligand has a major impact on aromatase inhibitory activity. Compounds with small group substitution on thiazole are found potentially may be used for the treatment of anti-breast cancer orally.Communicated by Ramaswamy H. Sarma.
{"title":"Novel oxadiazole-thiadiazole derivatives: synthesis, biological evaluation, and <i>in silico</i> studies.","authors":"Asaf Evrim Evren, Demokrat Nuha, Sam Dawbaa, Abdullah Burak Karaduman, Begüm Nurpelin Sağlik, Leyla Yurttaş","doi":"10.1080/07391102.2023.2247087","DOIUrl":"10.1080/07391102.2023.2247087","url":null,"abstract":"<p><p>In the search for new anticancer agents, we synthesized a new series of thiazole derivatives carried on thiadiazole-oxadiazole hybrid. Final compounds (<b>5a-5i</b>) were analyzed <i>via</i> <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted <i>via in silico</i> calculations. Their anticancer properties were determined using MTT method against MCF7 and A549 cell lines. Compounds <b>5a</b>, <b>5b</b> and <b>5c</b> were found more active against MCF7 cells than A549 cells while they were not cytotoxic on L929 healthy cells. Generally, it can be summarized that acetamide moiety has a pivotal role in anticancer activity. For further studies, their aromatase inhibitory activity was evaluated. After determination all these features, the binding modes of the active compounds and the stability and relation of the ligand-enzyme complex were investigated using molecular docking and molecular dynamics simulation studies, respectively. <i>In vitro</i> and <i>in silico</i> studies suggest two important structure-activity relationship (SAR) points that at least one azole ring is essential, and if there is approximately 8.0 ± 0.5 Å distance between the H-bond rich zone of ligand and the heteroaryl ring system of ligand has a major impact on aromatase inhibitory activity. Compounds with small group substitution on thiazole are found potentially may be used for the treatment of anti-breast cancer orally.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10014620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2023-08-22DOI: 10.1080/07391102.2023.2249103
Mazumder Adhish, I Manjubala
The cysteine-knot containing negative regulator of the Wnt (Wingless-related integration site) signaling pathway, sclerostin (SOST) is an emerging therapeutic target for osteoporosis. Its inhibition is responsible for the promotion of osteoblastogenesis. In this study, taurine, an amino sulfonic acid was used to study its mechanism of action for the inhibition of the SOST protein. Molecular docking and dynamic studies were performed as a part of the study whereby, it was observed that taurine binds to a probable allosteric pocket which allows it to modulate the structure of the SOST protein affecting all of the loops - loops 1, loop 2, and loop 3 - as well as the cysteine residues forming the cysteine-knot. The study also identified a set of seven taurine analogues that have better pharmacological activity than their parent compound using screening techniques. The conclusions derived from the study support that taurine has a probable antagonistic effect on the SOST protein directly through the modulation of HNQS motif and loops 2 and 3 and indirectly through its influence on the cysteine residues - 134, 165 and 167 C. Based on the results, it can be assumed that the binding of taurine with SOST protein probably reduces its binding affinity to the LRP6 protein greatly, while also inhibiting the target protein from anchoring to LRP4. Furthermore, it was noted that probable additional binding with any small molecule inhibitor (SMI) at the active site (PNAIG motif), in the presence of an already allosterically bound taurine, of the SOST protein would result in a complete potential antagonism of the target protein. Additionally, the study also uncovers the possible role of the GKWWRPS motif in providing stability to the PNAIG motif for the purpose of binding with LRP6.Communicated by Ramaswamy H. Sarma.
{"title":"An in-silico approach to the potential modulatory effect of taurine on sclerostin (SOST) and its probable role during osteoporosis.","authors":"Mazumder Adhish, I Manjubala","doi":"10.1080/07391102.2023.2249103","DOIUrl":"10.1080/07391102.2023.2249103","url":null,"abstract":"<p><p>The cysteine-knot containing negative regulator of the Wnt (Wingless-related integration site) signaling pathway, sclerostin (SOST) is an emerging therapeutic target for osteoporosis. Its inhibition is responsible for the promotion of osteoblastogenesis. In this study, taurine, an amino sulfonic acid was used to study its mechanism of action for the inhibition of the SOST protein. Molecular docking and dynamic studies were performed as a part of the study whereby, it was observed that taurine binds to a probable allosteric pocket which allows it to modulate the structure of the SOST protein affecting all of the loops - loops 1, loop 2, and loop 3 - as well as the cysteine residues forming the cysteine-knot. The study also identified a set of seven taurine analogues that have better pharmacological activity than their parent compound using screening techniques. The conclusions derived from the study support that taurine has a probable antagonistic effect on the SOST protein directly through the modulation of HNQS motif and loops 2 and 3 and indirectly through its influence on the cysteine residues - 134, 165 and 167 C. Based on the results, it can be assumed that the binding of taurine with SOST protein probably reduces its binding affinity to the LRP6 protein greatly, while also inhibiting the target protein from anchoring to LRP4. Furthermore, it was noted that probable additional binding with any small molecule inhibitor (SMI) at the active site (PNAIG motif), in the presence of an already allosterically bound taurine, of the SOST protein would result in a complete potential antagonism of the target protein. Additionally, the study also uncovers the possible role of the GKWWRPS motif in providing stability to the PNAIG motif for the purpose of binding with LRP6.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10555797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prostate Cancer (PCa) is an abnormal cell growth within the prostate. This condition is the second most widespread malignancy in elderly males and one of the most frequently diagnosed life-threatening conditions. The Androgen receptor signaling pathway played a crucial role in the initiation and spread to increase the risk of PCa. Hence, targeting the AR receptor signaling pathway is a key strategy for a therapeutic plan for PCa. Our study focuses on recognizing potential inhibitors for dual targeting in PCa by using the in-silico approach. In this study, we target the two enzymes that are CYP17A1 (3RUK) and 5α-reductase (3G1R) responsible for PCa, with the help of phytoconstituents. The natural plant contains various phytochemical types produced from secondary metabolites and used as a medical treatment. The in-silico investigation of phytoconstituents and enzymes was done by approaching molecular docking, ADMET analysis, and high-level molecular dynamic simulation used to assess the stability and binding affinities of the protein-ligand complex. Some phytoconstituents, such as Peonidin, Pelargonidin, Malvidin and Berberine show complex has good molecular interaction with protein. The reliability of the docking scores was examined using a molecular dynamic simulation, which revealed that the complex remained stable throughout the simulation, which ranged from 0 to 200 ns. The selected hits may be effective against CYP17A1 (3RUK) and 5α-reductase (3G1R) (PCa) using a computer-aided drug design (CADD) method, which further enables researchers for upcoming in-vivo and in-vitro research, according to our in-silico approach.Communicated by Ramaswamy H. Sarma.
{"title":"Dual targeting in prostate cancer with phytoconstituents as a potent lead: a computational approach for novel drug discovery.","authors":"Sachin A Dhawale, Pallavi Bhosle, Sadhana Mahajan, Geetanjali Patil, Sachin Gawale, Mangesh Ghodke, Ganesh Tapadiya, Azim Ansari","doi":"10.1080/07391102.2023.2251059","DOIUrl":"10.1080/07391102.2023.2251059","url":null,"abstract":"<p><p>Prostate Cancer (PCa) is an abnormal cell growth within the prostate. This condition is the second most widespread malignancy in elderly males and one of the most frequently diagnosed life-threatening conditions. The Androgen receptor signaling pathway played a crucial role in the initiation and spread to increase the risk of PCa. Hence, targeting the AR receptor signaling pathway is a key strategy for a therapeutic plan for PCa. Our study focuses on recognizing potential inhibitors for dual targeting in PCa by using the <i>in-silico</i> approach. In this study, we target the two enzymes that are CYP17A1 (3RUK) and 5α-reductase (3G1R) responsible for PCa, with the help of phytoconstituents. The natural plant contains various phytochemical types produced from secondary metabolites and used as a medical treatment. The <i>in-silico</i> investigation of phytoconstituents and enzymes was done by approaching molecular docking, ADMET analysis, and high-level molecular dynamic simulation used to assess the stability and binding affinities of the protein-ligand complex. Some phytoconstituents, such as Peonidin, Pelargonidin, Malvidin and Berberine show complex has good molecular interaction with protein. The reliability of the docking scores was examined using a molecular dynamic simulation, which revealed that the complex remained stable throughout the simulation, which ranged from 0 to 200 ns. The selected hits may be effective against CYP17A1 (3RUK) and 5α-reductase (3G1R) (PCa) using a computer-aided drug design (CADD) method, which further enables researchers for upcoming in-vivo and in-vitro research, according to our <i>in-silico</i> approach.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10121326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}