Pub Date : 2024-11-01Epub Date: 2023-08-30DOI: 10.1080/07391102.2023.2252908
Md Jahirul Islam, Md Siddik Alom, Md Shahadat Hossain, Md Ackas Ali, Shaila Akter, Shafiqul Islam, M Obayed Ullah, Mohammad A Halim
ORF3a is a conserved accessory protein of SARS-CoV-2, linked to viral infection and pathogenesis, with acquired mutations at various locations. Previous studies have shown that the occurrence of the Q57H mutation is higher in comparison to other positions in ORF3a. This mutation is known to induce conformational changes, yet the extent of structural alteration and its role in the viral adaptation process remain unknown. Here we performed molecular dynamics (MD) simulations of wt-ORF3a, Q57H, and Q57A mutants to analyze structural changes caused by mutations compared to the native protein. The MD analysis revealed that Q57H and Q57A mutants show significant structural changes in the dimer conformation than the wt-ORF3a. This dimer conformer narrows down the ion channel cavity, which reduces Na + or K + permeability leading to decrease the antigenic response that can help the virus to escape the host immune system. Non-bonding interaction analysis shows the Q57H mutant has more interacting residues, resulting in more stability within dimer conformation than the wt-ORF3a and Q57A. Moreover, both mutant dimers (Q57H and Q57A) form a novel salt-bridge interaction at the same position between A:Asp142 and B:Lys61, whereas such an interaction is absent in the wt-ORF3a dimer. We have also noticed that the TM3 domain's flexibility in Q57H is increased because of strong inter-domain interactions of TM1 and TM2 within the dimer conformation. These unusual interactions and flexibility of Q57H mutant can have significant impacts on the SARS-CoV-2 adaptations, virulence, transmission, and immune system evasion. Our findings are consistent with the previous experimental data and provided details information on the structural perturbation in ORF3a caused by mutations, which can help better understand the structural change at the molecular level as well as the reason for the high virulence properties of this variant.Communicated by Ramaswamy H. Sarma.
ORF3a是SARS-CoV-2的一种保守的辅助蛋白,与病毒感染和发病机制有关,并在不同位置发生获得性突变。先前的研究表明,与ORF3a的其他位置相比,Q57H突变的发生率更高。已知这种突变可诱导构象变化,但结构改变的程度及其在病毒适应过程中的作用尚不清楚。在这里,我们对wt-ORF3a、Q57H和Q57A突变体进行了分子动力学(MD)模拟,以分析与天然蛋白相比,突变引起的结构变化。MD分析显示,与wt-ORF3a相比,Q57H和Q57A突变体的二聚体构象发生了显著的结构变化。这种二聚体构象缩小了离子通道腔,从而降低了Na +或K +的渗透性,从而减少了抗原反应,从而帮助病毒逃离宿主免疫系统。非键相互作用分析表明,与wt-ORF3a和Q57A相比,Q57H突变体具有更多的相互作用残基,在二聚体构象内具有更高的稳定性。此外,两种突变二聚体(Q57H和Q57A)在a:Asp142和B:Lys61之间的相同位置形成了一种新的盐桥相互作用,而wt-ORF3a二聚体中没有这种相互作用。我们还注意到,TM3结构域的灵活性在Q57H中增加,因为TM1和TM2在二聚体构象中具有很强的结构域间相互作用。Q57H突变体的这些不寻常的相互作用和灵活性可能对SARS-CoV-2的适应性、毒力、传播和免疫系统逃避产生重大影响。我们的发现与之前的实验数据一致,提供了突变引起ORF3a结构扰动的详细信息,有助于更好地了解该变异在分子水平上的结构变化以及该变异具有高毒力特性的原因。由Ramaswamy H. Sarma传达。
{"title":"Unraveling the impact of ORF3a Q57H mutation on SARS-CoV-2: insights from molecular dynamics.","authors":"Md Jahirul Islam, Md Siddik Alom, Md Shahadat Hossain, Md Ackas Ali, Shaila Akter, Shafiqul Islam, M Obayed Ullah, Mohammad A Halim","doi":"10.1080/07391102.2023.2252908","DOIUrl":"10.1080/07391102.2023.2252908","url":null,"abstract":"<p><p>ORF3a is a conserved accessory protein of SARS-CoV-2, linked to viral infection and pathogenesis, with acquired mutations at various locations. Previous studies have shown that the occurrence of the Q57H mutation is higher in comparison to other positions in ORF3a. This mutation is known to induce conformational changes, yet the extent of structural alteration and its role in the viral adaptation process remain unknown. Here we performed molecular dynamics (MD) simulations of wt-ORF3a, Q57H, and Q57A mutants to analyze structural changes caused by mutations compared to the native protein. The MD analysis revealed that Q57H and Q57A mutants show significant structural changes in the dimer conformation than the wt-ORF3a. This dimer conformer narrows down the ion channel cavity, which reduces Na + or K + permeability leading to decrease the antigenic response that can help the virus to escape the host immune system. Non-bonding interaction analysis shows the Q57H mutant has more interacting residues, resulting in more stability within dimer conformation than the wt-ORF3a and Q57A. Moreover, both mutant dimers (Q57H and Q57A) form a novel salt-bridge interaction at the same position between A:Asp142 and B:Lys61, whereas such an interaction is absent in the wt-ORF3a dimer. We have also noticed that the TM3 domain's flexibility in Q57H is increased because of strong inter-domain interactions of TM1 and TM2 within the dimer conformation. These unusual interactions and flexibility of Q57H mutant can have significant impacts on the SARS-CoV-2 adaptations, virulence, transmission, and immune system evasion. Our findings are consistent with the previous experimental data and provided details information on the structural perturbation in ORF3a caused by mutations, which can help better understand the structural change at the molecular level as well as the reason for the high virulence properties of this variant.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10113028","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}
Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aβ) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aβ degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aβ build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aβ load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aβ accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.
{"title":"Integrated in-silico and in-vitro assessments of HDAC6 inhibitor efficacy in mitigating amyloid beta pathology in Alzheimer's disease.","authors":"Gajendra Choudhary, Manisha Prajapat, Gurjeet Kaur, Harvinder Singh, Saniya Mahendiratta, Ajay Prakash, Bikash Medhi","doi":"10.1080/07391102.2023.2274518","DOIUrl":"10.1080/07391102.2023.2274518","url":null,"abstract":"<p><p>Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aβ) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aβ degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aβ build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aβ load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aβ accumulation <i>via</i> NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50158049","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}
Almost 80% of lung cancer diagnoses each year correspond to non-small cell lung cancer (NSCLC). The percentage of NSCLC with EGFR overexpression ranges from 40% to 89%, with squamous tumors showing the greatest rates (89%) and adenocarcinomas showing the lowest rates (41%). Therefore, in NSCLC therapy, blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization to develop EGFR-TK inhibitors. However, the associated limitation such as resistance and genetic mutation along with adverse effects, constrained the long-term treatment and effectiveness of such medication. Therefore, in recent years, pyrimidine derivatives were uncovered as potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed structure-activity relationship, biological evaluation, and comparative docking studies of pyrimidine compounds. We have added the comparative docking analysis followed by the molecular simulation study against the four different PDBs of EGFR to strengthen the already existing research. Docking analysis unfolded that compound 14 resulted as noticeable with all different PDB and managed to interact with some of the crucial amino acid residues. From a future perspective, researchers must develop a more selective inhibitor, that can selectively target the mutation. Our review will support medicinal chemists in the direction of the development of novel pyrimidine-based EGFR TKIs.Communicated by Ramaswamy H. Sarma.
每年几乎80%的肺癌诊断为非小细胞肺癌(NSCLC)。EGFR过表达的非小细胞肺癌比例从40%到89%不等,鳞状肿瘤的比例最高(89%),腺癌的比例最低(41%)。因此,在NSCLC治疗中,通过抑制EGFR细胞内酪氨酸激酶结构域来阻断EGFR驱动通路已显示出显著的改善。在这种观点下,一些小分子特别是嘧啶/融合嘧啶支架被用于分子杂交以开发EGFR-TK抑制剂。然而,相关的限制,如耐药性和基因突变以及不良反应,限制了这种药物的长期治疗和有效性。因此,近年来,嘧啶衍生物被发现是潜在的EGFR TKIs。本文综述了EGFR TKIs在与嘧啶类化合物的构效关系、生物学评价和比较对接等方面的研究进展。我们增加了EGFR四种不同PDBs的比较对接分析和分子模拟研究,以加强已有的研究。对接分析显示,化合物14与所有不同的PDB都有显著的相互作用,并成功地与一些关键氨基酸残基相互作用。从未来的角度来看,研究人员必须开发一种更具选择性的抑制剂,可以选择性地靶向突变。我们的综述将支持药物化学家朝着开发新型基于嘧啶的EGFR TKIs的方向发展。由Ramaswamy H. Sarma传达。
{"title":"An outlook of docking analysis and structure-activity relationship of pyrimidine-based analogues as EGFR inhibitors against non-small cell lung cancer (NSCLC).","authors":"Rohit Pal, Ghanshyam Teli, Sindhuja Sengupta, Lalmohan Maji, Gurubasavaraja Swamy Purawarga Matada","doi":"10.1080/07391102.2023.2252082","DOIUrl":"10.1080/07391102.2023.2252082","url":null,"abstract":"<p><p>Almost 80% of lung cancer diagnoses each year correspond to non-small cell lung cancer (NSCLC). The percentage of NSCLC with EGFR overexpression ranges from 40% to 89%, with squamous tumors showing the greatest rates (89%) and adenocarcinomas showing the lowest rates (41%). Therefore, in NSCLC therapy, blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization to develop EGFR-TK inhibitors. However, the associated limitation such as resistance and genetic mutation along with adverse effects, constrained the long-term treatment and effectiveness of such medication. Therefore, in recent years, pyrimidine derivatives were uncovered as potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed structure-activity relationship, biological evaluation, and comparative docking studies of pyrimidine compounds. We have added the comparative docking analysis followed by the molecular simulation study against the four different PDBs of EGFR to strengthen the already existing research. Docking analysis unfolded that compound <b>14</b> resulted as noticeable with all different PDB and managed to interact with some of the crucial amino acid residues. From a future perspective, researchers must develop a more selective inhibitor, that can selectively target the mutation. Our review will support medicinal chemists in the direction of the development of novel pyrimidine-based EGFR TKIs.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10114765","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 : 2024-11-01Epub Date: 2023-09-01DOI: 10.1080/07391102.2023.2252091
Shraddha Ram, Pallavi More-Adate, Amol A Tagalpallewar, Anil T Pawar, Shuchi Nagar, Akshay M Baheti
Uncontrolled cell proliferation is a common definition of cancer. After lung carcinoma, breast neoplasm is the second-most prevalent kind of cancer. The majority of breast cancer cells and healthy breast cells both have receptors for circulating oestrogen and progesterone. In order to promote the development and division of cancer cells, oestrogen and progesterone bind to the receptors and may collaborate with growth factors (such as oncogenes and mutant tumour suppressor genes). As per the literature, Tecteria coadunata (Wall.) C. Chr. has anticancer, antioxidant and anti-inflammatory potential. After the hydroalcoholic extraction of this rhizome, total of 200 phytochemicals were retrieved from HR-LCMS analysis. In this current study, Network pharmacology was carried out to explore the rationale of Tecteria coadunata (Wall.) C. Chr. by using different database using Cytoscape software. The network depicted the interaction of Bioactives with their targets and their association with several disease, especially breast cancer. Tecteria coadunata (Wall.) C. Chr. has offered new relationship with variety of genes and its applications in different types of breast cancers. Further Gene Ontology was carried out and it showed key targets were TP53, BRCA2, PGR and CHEK 2. Further Signalling pathways were also enriched. Flex-X software was used for molecular docking studies, and it verified that Dopaxanthin, Dantrolene and Orotidin shows the highest binding affinities with key targets. Additionally, Pharmacokinetic analysis revealed that all top three lead compounds which follows the Lipinski Rule (Rule of three) without interrupting the conditions of bioavailability with minimal toxicity.Communicated by Ramaswamy H. Sarma.
不受控制的细胞增殖是癌症的常见定义。继肺癌之后,乳腺癌是第二常见的癌症。大多数乳腺癌细胞和健康乳腺细胞都有循环雌激素和黄体酮的受体。为了促进癌细胞的发育和分裂,雌激素和孕激素与受体结合,并可能与生长因子(如癌基因和突变的肿瘤抑制基因)协同作用。根据文献,Tecteria coadunata (Wall.)空空的。具有抗癌、抗氧化和抗炎的潜力。水醇提取后,经HR-LCMS分析,共检出200种植物化学成分。本研究以网络药理学为基础,探讨其药理作用的基本原理。空空的。通过使用Cytoscape软件使用不同的数据库。该网络描述了生物活性物与其靶点的相互作用,以及它们与几种疾病,特别是乳腺癌的关联。壁虎(壁虎)空空的。提供了与多种基因的新关系及其在不同类型乳腺癌中的应用。进一步开展基因本体研究,发现关键靶点为TP53、BRCA2、PGR和CHEK 2。进一步的信号通路也丰富了。利用Flex-X软件进行分子对接研究,验证Dopaxanthin、Dantrolene和Orotidin与关键靶点的结合亲和力最高。此外,药代动力学分析显示,所有前三先导化合物均符合Lipinski规则(三规则),且不中断生物利用度条件,毒性最小。由Ramaswamy H. Sarma传达。
{"title":"An <i>in-silico</i> investigation and network pharmacology based approach to explore the anti-breast-cancer potential of <i>Tecteria coadunata</i> (Wall.) C. Chr.","authors":"Shraddha Ram, Pallavi More-Adate, Amol A Tagalpallewar, Anil T Pawar, Shuchi Nagar, Akshay M Baheti","doi":"10.1080/07391102.2023.2252091","DOIUrl":"10.1080/07391102.2023.2252091","url":null,"abstract":"<p><p>Uncontrolled cell proliferation is a common definition of cancer. After lung carcinoma, breast neoplasm is the second-most prevalent kind of cancer. The majority of breast cancer cells and healthy breast cells both have receptors for circulating oestrogen and progesterone. In order to promote the development and division of cancer cells, oestrogen and progesterone bind to the receptors and may collaborate with growth factors (such as oncogenes and mutant tumour suppressor genes). As per the literature, <i>Tecteria coadunata</i> (Wall.) C. Chr. has anticancer, antioxidant and anti-inflammatory potential. After the hydroalcoholic extraction of this rhizome, total of 200 phytochemicals were retrieved from HR-LCMS analysis. In this current study, Network pharmacology was carried out to explore the rationale of <i>Tecteria coadunata</i> (Wall.) C. Chr. by using different database using Cytoscape software. The network depicted the interaction of Bioactives with their targets and their association with several disease, especially breast cancer. <i>Tecteria coadunata</i> (Wall.) C. Chr. has offered new relationship with variety of genes and its applications in different types of breast cancers. Further Gene Ontology was carried out and it showed key targets were TP53, BRCA2, PGR and CHEK 2. Further Signalling pathways were also enriched. Flex-X software was used for molecular docking studies, and it verified that Dopaxanthin, Dantrolene and Orotidin shows the highest binding affinities with key targets. Additionally, Pharmacokinetic analysis revealed that all top three lead compounds which follows the Lipinski Rule (Rule of three) without interrupting the conditions of bioavailability with minimal toxicity.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10185782","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 : 2024-11-01Epub Date: 2023-08-29DOI: 10.1080/07391102.2023.2252090
Taufik Muhammad Fakih
The present study aimed to strategically design a Molecularly Imprinted Polymer (MIP) with selective extraction capabilities for volatile compounds found in pork. These specific volatile compounds, such as 3-methyl-1-butanol, 1-nonanal, octanal, hexanal, 2-pentyl-furan, 1-penten-3-one, N-morpholinomethyl-isopropyl-sulfide, methyl butyrate, and (E,E)-2,4-decadienal, are primarily responsible for the distinctive aroma and flavor characteristics associated with pork. Molecular dynamics simulations were employed to investigate the stability of the pre-polymerization system, simulating the interactions between the volatile compounds as templates, 4-hydroxyethyl methacrylate (HEMA) as monomers, and ethylene glycol dimethacrylate (EGDMA) as crosslinkers. Computational simulations revealed that the optimal mole ratio of 1:4:20 for templates, monomers, and crosslinkers resulted in the most favorable functional radial distribution and exhibited the strongest interactions. To validate the computational findings, additional analyses were performed utilizing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA), radial distribution function (RDF), and hydrogen bond (HBond) occupancy. The calculated binding free energy demonstrated that all template molecules were capable to bind with both the monomers and crosslinkers, including 1-penten-3-one and N-morpholinomethyl-isopropyl-sulfide displaying the strongest interactions, with values of -12,674 kJ/mol and -11,646 kJ/mol, respectively. The congruence between the results obtained from the molecular simulation analyses highlights the crucial role of molecular dynamics simulations in the study and development of MIP for the analysis of marker compounds present in pork.Communicated by Ramaswamy H. Sarma.
{"title":"Molecularly imprinted polymer-based sensors for identification volatile compounds in pharmaceutical products: in silico rational design.","authors":"Taufik Muhammad Fakih","doi":"10.1080/07391102.2023.2252090","DOIUrl":"10.1080/07391102.2023.2252090","url":null,"abstract":"<p><p>The present study aimed to strategically design a Molecularly Imprinted Polymer (MIP) with selective extraction capabilities for volatile compounds found in pork. These specific volatile compounds, such as 3-methyl-1-butanol, 1-nonanal, octanal, hexanal, 2-pentyl-furan, 1-penten-3-one, N-morpholinomethyl-isopropyl-sulfide, methyl butyrate, and (E,E)-2,4-decadienal, are primarily responsible for the distinctive aroma and flavor characteristics associated with pork. Molecular dynamics simulations were employed to investigate the stability of the pre-polymerization system, simulating the interactions between the volatile compounds as templates, 4-hydroxyethyl methacrylate (HEMA) as monomers, and ethylene glycol dimethacrylate (EGDMA) as crosslinkers. Computational simulations revealed that the optimal mole ratio of 1:4:20 for templates, monomers, and crosslinkers resulted in the most favorable functional radial distribution and exhibited the strongest interactions. To validate the computational findings, additional analyses were performed utilizing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA), radial distribution function (RDF), and hydrogen bond (HBond) occupancy. The calculated binding free energy demonstrated that all template molecules were capable to bind with both the monomers and crosslinkers, including 1-penten-3-one and N-morpholinomethyl-isopropyl-sulfide displaying the strongest interactions, with values of -12,674 kJ/mol and -11,646 kJ/mol, respectively. The congruence between the results obtained from the molecular simulation analyses highlights the crucial role of molecular dynamics simulations in the study and development of MIP for the analysis of marker compounds present in pork.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10103249","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 : 2024-11-01Epub Date: 2023-08-29DOI: 10.1080/07391102.2023.2252072
Kaushik Sarkar, Subrata Nandi, Rajesh Kumar Das
Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (-10.8 kcal/mol), followed by baloxavir marboxil (-10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein-ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be -61.724 kJ/mol and -48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV.Communicated by Ramaswamy H. Sarma.
{"title":"Computational insights into pediatric adenovirus inhibitors: <i>in silico</i> strategies for drug repurposing.","authors":"Kaushik Sarkar, Subrata Nandi, Rajesh Kumar Das","doi":"10.1080/07391102.2023.2252072","DOIUrl":"10.1080/07391102.2023.2252072","url":null,"abstract":"<p><p>Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (-10.8 kcal/mol), followed by baloxavir marboxil (-10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein-ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be -61.724 kJ/mol and -48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109431","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 : 2024-11-01Epub Date: 2023-09-07DOI: 10.1080/07391102.2023.2252914
Musa Erdoğan, Ferah Comert Onder
To create some novel anticancer molecules, a library of novel series of various triazoles linked to the hydroxyl group of 5,6,7,8-tetrafluoronaphthalen-1-ol (3) was designed and synthesized via CuAAC reaction 'Click Chemistry' of tetrafluoronaphthalene based terminal alkyne with substituted organic azides. The structural characterizations of the targeted Click products 9-18 were confirmed by FTIR, 1H NMR, 19F NMR, 13C NMR and HRMS spectroscopy. Synthesized compounds were tested in two triple negative breast cancer (TNBC) cell lines to understand their anticancer potentials. According to our findings, compounds 14 and 13 showed high cytotoxicity in BT549 cells at 20 μM and 30 μM, respectively. Moreover, these compounds blocked the migration of BT549 cells. In the MDA-MB-231 cell line, compound 18 exhibited high cytotoxicity and can block cell migration for 24 h. Molecular docking study with synthesized novel compounds was performed by Glide/SP method against SphK1 drug target. Furthermore, molecular dynamics (MD) simulation was carried out for the compounds 12-14 and 18. The compounds 13 and 14 may be potential inhibitor candidates in place of a reference inhibitor. A pharmacophore model was generated with the most potent compound 14, and the approved drugs were screened using the modules of Discovery Studio to find similar drugs. Consequently, this comprehensive study encompassing design, synthesis, in vitro and in silico analyses were correlated with the structure-activity relationship between compounds. The findings have the potential to unveil promising drug candidates for future studies.Communicated by Ramaswamy H. Sarma.
{"title":"Synthesis, anticancer activity and molecular modeling study of novel substituted triazole linked tetrafluoronaphthalene hybrid derivatives.","authors":"Musa Erdoğan, Ferah Comert Onder","doi":"10.1080/07391102.2023.2252914","DOIUrl":"10.1080/07391102.2023.2252914","url":null,"abstract":"<p><p>To create some novel anticancer molecules, a library of novel series of various triazoles linked to the hydroxyl group of 5,6,7,8-tetrafluoronaphthalen-1-ol <b>(3)</b> was designed and synthesized <i>via</i> CuAAC reaction '<i>Click Chemistry'</i> of tetrafluoronaphthalene based terminal alkyne with substituted organic azides. The structural characterizations of the targeted Click products <b>9-18</b> were confirmed by FTIR, <sup>1</sup>H NMR, <sup>19</sup>F NMR, <sup>13</sup>C NMR and HRMS spectroscopy. Synthesized compounds were tested in two triple negative breast cancer (TNBC) cell lines to understand their anticancer potentials. According to our findings, compounds <b>14</b> and <b>13</b> showed high cytotoxicity in BT549 cells at 20 μM and 30 μM, respectively. Moreover, these compounds blocked the migration of BT549 cells. In the MDA-MB-231 cell line, compound <b>18</b> exhibited high cytotoxicity and can block cell migration for 24 h. Molecular docking study with synthesized novel compounds was performed by Glide/SP method against SphK1 drug target. Furthermore, molecular dynamics (MD) simulation was carried out for the compounds <b>12-14</b> and <b>18</b>. The compounds <b>13</b> and <b>14</b> may be potential inhibitor candidates in place of a reference inhibitor. A pharmacophore model was generated with the most potent compound <b>14</b>, and the approved drugs were screened using the modules of Discovery Studio to find similar drugs. Consequently, this comprehensive study encompassing design, synthesis, <i>in vitro</i> and <i>in silico</i> analyses were correlated with the structure-activity relationship between compounds. The findings have the potential to unveil promising drug candidates for future studies.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168516","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 : 2024-11-01Epub Date: 2023-08-30DOI: 10.1080/07391102.2023.2252077
Kiran Kumar A, R S Rathore
Protein-protein and protein-peptide interactions (PPI and PPepI) belong to a similar category of interactions, yet seemingly subtle differences exist among them. To characterize differences between protein-protein (PP) and protein-peptide (PPep) interactions, we have focussed on two important classes of residues-hotspot and anchor residues. Using implicit solvation-based free energy calculations, a very large-scale alanine scanning has been performed on benchmark datasets, consisting of over 5700 interface residues. The differences in the two categories are more pronounced, if the data were divided into three distinct types, namely - weak hotspots (having binding free energy loss upon Ala mutation, ΔΔG, ∼2-10 kcal/mol), moderate hotspots (ΔΔG, ∼10-20 kcal/mol) and strong hotspots (ΔΔG ≥ ∼20 kcal/mol). The analysis suggests that for PPI, weak hotspots are predominantly populated by polar and hydrophobic residues. The distribution shifts towards charged and polar residues for moderate hotspot and charged residues (principally Arg) are overwhelmingly present in the strong hotspot. On the other hand, in the PPepI dataset, the distribution shifts from predominantly hydrophobic and polar (in the weak type) to almost similar preference for polar, hydrophobic and charged residues (in moderate type) and finally the charged residue (Arg) and Trp are mostly occupied in the strong type. The preferred anchor residues in both categories are Arg, Tyr and Leu, possessing bulky side chain and which also strike a delicate balance between side chain flexibility and rigidity. The present knowledge should aid in effective design of biologics, by augmentation or disruption of PPIs with peptides or peptidomimetics.Communicated by Ramaswamy H. Sarma.
{"title":"Categorization of hotspots into three types - weak, moderate and strong to distinguish protein-protein <i>versus</i> protein-peptide interactions.","authors":"Kiran Kumar A, R S Rathore","doi":"10.1080/07391102.2023.2252077","DOIUrl":"10.1080/07391102.2023.2252077","url":null,"abstract":"<p><p>Protein-protein and protein-peptide interactions (PPI and PPepI) belong to a similar category of interactions, yet seemingly subtle differences exist among them. To characterize differences between protein-protein (PP) and protein-peptide (PPep) interactions, we have focussed on two important classes of residues-hotspot and anchor residues. Using implicit solvation-based free energy calculations, a very large-scale alanine scanning has been performed on benchmark datasets, consisting of over 5700 interface residues. The differences in the two categories are more pronounced, if the data were divided into three distinct types, namely - weak hotspots (having binding free energy loss upon Ala mutation, ΔΔG, ∼2-10 kcal/mol), moderate hotspots (ΔΔG, ∼10-20 kcal/mol) and strong hotspots (ΔΔG ≥ ∼20 kcal/mol). The analysis suggests that for PPI, weak hotspots are predominantly populated by polar and hydrophobic residues. The distribution shifts towards charged and polar residues for moderate hotspot and charged residues (principally Arg) are overwhelmingly present in the strong hotspot. On the other hand, in the PPepI dataset, the distribution shifts from predominantly hydrophobic and polar (in the weak type) to almost similar preference for polar, hydrophobic and charged residues (in moderate type) and finally the charged residue (Arg) and Trp are mostly occupied in the strong type. The preferred anchor residues in both categories are Arg, Tyr and Leu, possessing bulky side chain and which also strike a delicate balance between side chain flexibility and rigidity. The present knowledge should aid in effective design of biologics, by augmentation or disruption of PPIs with peptides or peptidomimetics.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10476954","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 : 2024-10-21DOI: 10.1080/07391102.2024.2417226
David Kikaawa, E Vadivel
Leishmaniasis treatment primarily relies on chemotherapy due to lack of vaccines. However, the low efficacy, parasite resistance, and toxicity associated with existing drugs necessitate the development of effective and safer therapies. Fuchino et al. reported promising leishmanicidal activity in a series of benzo[c]phenanthridines against L. major promastigotes. To progress these compounds towards drug development, it is crucial to understand their molecular targets, mechanisms of action, binding interactions, and structural requirements. In this research, molecular docking, network pharmacology, 2D-QSAR, and 3D-QSAR CoMFA studies were performed on 30 benzo[c]phenanthridines. Docking analysis showed that all molecules had a strong binding affinity to L. major-nucleoside diphosphate kinase (NDPK) compared to the other targets. 10-isopropoxy sanguinarine had the highest binding affinity (-10.6 kcal/mol) and formed ionic and hydrophobic interactions. Network pharmacology analysis of the most active compounds identified serine/threonine-protein kinase Mtor as a potential antileishmaniasis target in humans for benzo[c]phenanthridines. This was confirmed with high-affinity scores > -7.0 kcal/mol for all the compounds docked. GO and KEGG pathway enrichment identified Reg. of fatty acid oxidation (BP), TORC1 complex (CC), RNA polymerase III type 1 promoter sequence-specific DNA binding (MF), and Acute myeloid leukemia (KEGG pathway) to be highly enriched with the hub genes. Both 2D and 3D-QSAR CoMFA models satisfied the internal and external validation tests as follows: 2D-QSAR: R2Train = 0.9040, Q2cv = 0.8648, R2adj = 0.8838, and R2Test = 0.8740; and 3D-QSAR: r2 = 0.998, q2 = 0.526, and SDEP = 0.856. The molecules can be practically evaluated as superior antileishmaniasis agents.
由于缺乏疫苗,利什曼病的治疗主要依靠化疗。然而,现有药物疗效低、寄生虫抗药性强、毒性大,因此有必要开发更有效、更安全的疗法。Fuchino 等人报告了一系列苯并[c]菲啶类化合物对大鼠原虫具有良好的利什曼杀灭活性。为了推动这些化合物的药物开发,了解它们的分子靶点、作用机制、结合相互作用和结构要求至关重要。本研究对 30 种苯并[c]菲啶类化合物进行了分子对接、网络药理学、二维-QSAR 和三维-QSAR CoMFA 研究。对接分析表明,与其他靶标相比,所有分子与 L. major 核苷二磷酸激酶(NDPK)都有很强的结合亲和力。10-isopropoxy sanguinarine 的结合亲和力最高(-10.6 kcal/mol),并形成离子和疏水相互作用。对最具活性的化合物进行的网络药理学分析发现,丝氨酸/苏氨酸蛋白激酶 Mtor 是苯并[c]菲啶类药物潜在的人体抗利什曼病靶点。所有对接化合物的高亲和力得分大于-7.0 kcal/mol,证实了这一点。通过 GO 和 KEGG 通路富集发现,脂肪酸氧化调节(BP)、TORC1 复合物(CC)、RNA 聚合酶 III 型 1 启动子序列特异性 DNA 结合(MF)和急性髓系白血病(KEGG 通路)与枢纽基因高度富集。二维和三维 QSAR CoMFA 模型均通过了如下内部和外部验证测试:二维-QSAR:R2Train = 0.9040,Q2cv = 0.8648,R2adj = 0.8838,R2Test = 0.8740;三维-QSAR:R2 = 0.998,Q2 = 0.526,SDEP = 0.856。这些分子可被实际评估为优良的抗利什曼病药。
{"title":"Molecular docking, network pharmacology, and QSAR modelling studies of benzo[c]phenanthridines - novel antileishmaniasis agents.","authors":"David Kikaawa, E Vadivel","doi":"10.1080/07391102.2024.2417226","DOIUrl":"https://doi.org/10.1080/07391102.2024.2417226","url":null,"abstract":"<p><p>Leishmaniasis treatment primarily relies on chemotherapy due to lack of vaccines. However, the low efficacy, parasite resistance, and toxicity associated with existing drugs necessitate the development of effective and safer therapies. Fuchino <i>et al</i>. reported promising leishmanicidal activity in a series of benzo[c]phenanthridines against <i>L. major</i> promastigotes. To progress these compounds towards drug development, it is crucial to understand their molecular targets, mechanisms of action, binding interactions, and structural requirements. In this research, molecular docking, network pharmacology, 2D-QSAR, and 3D-QSAR CoMFA studies were performed on 30 benzo[c]phenanthridines. Docking analysis showed that all molecules had a strong binding affinity to <i>L. major</i>-nucleoside diphosphate kinase (NDPK) compared to the other targets. 10-isopropoxy sanguinarine had the highest binding affinity (-10.6 kcal/mol) and formed ionic and hydrophobic interactions. Network pharmacology analysis of the most active compounds identified serine/threonine-protein kinase Mtor as a potential antileishmaniasis target in humans for benzo[c]phenanthridines. This was confirmed with high-affinity scores > -7.0 kcal/mol for all the compounds docked. GO and KEGG pathway enrichment identified Reg. of fatty acid oxidation (BP), TORC1 complex (CC), RNA polymerase III type 1 promoter sequence-specific DNA binding (MF), and Acute myeloid leukemia (KEGG pathway) to be highly enriched with the hub genes. Both 2D and 3D-QSAR CoMFA models satisfied the internal and external validation tests as follows: 2D-QSAR: R<sup>2</sup><sub>Train</sub> = 0.9040, Q<sup>2</sup>cv = 0.8648, R<sup>2</sup>adj = 0.8838, and R<sup>2</sup><sub>Test</sub> = 0.8740; and 3D-QSAR: r<sup>2</sup> = 0.998, q<sup>2</sup> = 0.526, and SDEP = 0.856. The molecules can be practically evaluated as superior antileishmaniasis agents.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466415","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}
One of the significant therapeutic targets for Alzheimer's disease (AD) is Glycogen Synthase Kinase-3β (GSK-3β). Inhibition of GSK-3β can prevent hyperphosphorylation of tau, and thus prevent formation and accumulation of neurofibrillary tangles and neuropil threads that block intracellular transport, trigger unfolded protein response, and increase oxidative stress, cumulatively leading to neurodegeneration. In this study, we have performed structure-based virtual screening of two small-molecule libraries from ChemDiv CNS databases using AutoDock Vina to identify hit molecules based on their binding affinities compared to that of an established GSK-3β inhibitor, indirubin-3'-monoxime (IMO). Pharmacoinformatic screening on SwissADME and pkCSM servers enabled identification of lead molecules with favorable pharmacoinformatic properties for drug likeliness, including blood brain barrier (BBB) permeability. Further, molecular dynamic simulations identified six candidate lead molecules that show stable complex formation with GSK-3β in dynamic state under physiological conditions. Principal component analysis of the dynamic state was used to plot Free Energy Landscapes (FELs) of GSK-3β-ligand complexes. STRIDE secondary structure analysis of the lowest energy conformations identified from FEL plots, and binding free energy calculations by Molecular Mechanics Poisson-Boltzmann Surface Area ((ΔGbind)MM-PBSA) of the simulation trajectories led to the identification of two ligands as potential lead molecules having favorable free energy landscape profiles as well as significantly lower (ΔGbind)MM-PBSA in dynamic state compared to that of reference inhibitor IMO. Hence, this study identifies two novel brain penetrant GSK-3β inhibitors that are likely to have therapeutic potential against Alzheimer's disease.
{"title":"Identification of novel brain penetrant GSK-3β inhibitors toward Alzheimer's disease therapy by virtual screening, molecular docking, dynamic simulation, and MMPBSA analysis.","authors":"Asmita Dasgupta, Kastro Kalidass, Shabnam Farisha, Rounak Saha, Sanjukta Ghosh, Dinakara Rao Ampasala","doi":"10.1080/07391102.2024.2411524","DOIUrl":"https://doi.org/10.1080/07391102.2024.2411524","url":null,"abstract":"<p><p>One of the significant therapeutic targets for Alzheimer's disease (AD) is Glycogen Synthase Kinase-3β (GSK-3β). Inhibition of GSK-3β can prevent hyperphosphorylation of tau, and thus prevent formation and accumulation of neurofibrillary tangles and neuropil threads that block intracellular transport, trigger unfolded protein response, and increase oxidative stress, cumulatively leading to neurodegeneration. In this study, we have performed structure-based virtual screening of two small-molecule libraries from ChemDiv CNS databases using AutoDock Vina to identify hit molecules based on their binding affinities compared to that of an established GSK-3β inhibitor, indirubin-3'-monoxime (IMO). Pharmacoinformatic screening on SwissADME and pkCSM servers enabled identification of lead molecules with favorable pharmacoinformatic properties for drug likeliness, including blood brain barrier (BBB) permeability. Further, molecular dynamic simulations identified six candidate lead molecules that show stable complex formation with GSK-3β in dynamic state under physiological conditions. Principal component analysis of the dynamic state was used to plot Free Energy Landscapes (FELs) of GSK-3β-ligand complexes. STRIDE secondary structure analysis of the lowest energy conformations identified from FEL plots, and binding free energy calculations by Molecular Mechanics Poisson-Boltzmann Surface Area ((<i>ΔG<sub>bind</sub></i>)<sub>MM-PBSA</sub>) of the simulation trajectories led to the identification of two ligands as potential lead molecules having favorable free energy landscape profiles as well as significantly lower (<i>ΔG<sub>bind</sub></i>)<sub>MM-PBSA</sub> in dynamic state compared to that of reference inhibitor IMO. Hence, this study identifies two novel brain penetrant GSK-3β inhibitors that are likely to have therapeutic potential against Alzheimer's disease.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466414","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}