In silico pharmacology最新文献

{"title":"Investigation of <i>Aframomum melegueta</i> compounds as ERK5 inhibitor related to breast cancer via molecular docking and dynamic simulation.","authors":"Paul Olamide Ottu, Olorunfemi Oyewole Babalola, Cecilia Oluwamodupe, Ayodeji Folasade Oluwatobiloba, Idayat Oyinkansola Kehinde, Olufemi Adebisi Akinola, Sulyman Olalekan Ibrahim, Olusola Olalekan Elekofehinti","doi":"10.1007/s40203-025-00304-w","DOIUrl":"10.1007/s40203-025-00304-w","url":null,"abstract":"<p><p>Breast cancer remains a global health challenge, with rising cases predicted in the coming decades. The complexity of breast cancer treatment arises from its complex nature, often involving multiple therapeutic strategies. One promising approach is targeting the ERK5 pathway, a key regulator in cancer cell proliferation and survival. In this study, we explored the anticancer potential of bioactive compounds from <i>Aframomum melegueta</i>, a plant traditionally used in West African medicine. The 3D structure of ERK5 (PDB ID: 4B99) was prepared and optimized using the Schrödinger Protein Preparation Wizard. Six phytochemicals from <i>Aframomum melegueta</i> were screened for their binding affinities to ERK5 using GlideXP docking. Dihydrogingerenone A,1-(3,4-dihydroxy-5-methoxyphenyl)-7-(3,4-dihydroxyphenyl) heptane-3,5-diyldiacetate and Dihydrogingerenone C emerged as the lead compound, demonstrating a high docking score of -  9.659 kcal/mol, -  9.383 kcal/mol, and - 8.264 kcal/mol compared to standard anticancer drugs like Docetaxel (- 4.175 kcal/mol) and Temozolomide (- 5.443 kcal/mol). Post-docking analyses using MM-GBSA free energy calculations confirmed the compound's high binding stability, with van der Waals interactions and hydrogen bonding at critical residues such as Met140 playing a significant role. Pharmacokinetic profiling using ADME analysis showed that our compounds exhibited favorable drug-likeness properties, adhering to Lipinski's Rule of Five without violations. QSAR modeling and molecular dynamics (MD) simulations further validated its pharmacological potential. These findings suggest that <i>Aframomum melegueta</i> contains bioactive compounds with strong potential as ERK5 inhibitors, offering a novel approach to breast cancer treatment.</p><p><strong>Graphical abstract: </strong>The molecular docking study of Dihydrogingerenone A, 1-(3, 4-dihydroxy-5-methoxyphenyl)-7-(3, 4-dihydroxyphenyl) heptane-3, 5-diyldiacetate, and Dihydrogingerenone C from <i>Aframomum melegueta</i> as effective breast cancer treatment.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"18"},"PeriodicalIF":0.0,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic exploration potential of adenosine receptor antagonists through pharmacophore ligand-based modelling and pharmacokinetics studies against Parkinson disease.","authors":"Abduljelil Ajala, Otaru Habiba Asipita, Abatyough Terungwa Michael, Murtala Taiwo Tajudeen, Ibrahim A Abdulganiyyu, Ramith Ramu","doi":"10.1007/s40203-025-00305-9","DOIUrl":"10.1007/s40203-025-00305-9","url":null,"abstract":"<p><p>Parkinson's Disease (PD) is a neurodegenerative disorder that primarily affects persons aged 65 and older. It leads to a decline in motor function as a result of the buildup of abnormal protein deposits called Lewy bodies in the brain. Existing therapies exhibit restricted effectiveness and undesirable side effects. The objective was to discover potent medications that have demonstrated effectiveness in treating PD by employing computational methods. This work employed a comprehensive approach to evaluate 70 pyrimidine derivatives for their potential in treating PD. The evaluation involved the use of QSAR modelling, virtual screening, molecular docking, MD simulation, ADMET analysis, and antagonist inhibitor creation. Six compounds passed all the evaluation, while for MD simulation, carried out between the compound with best docking score and the reference drug, compound 57 was discovered to possess more stability compared to theophylline which is the reference drug, and it functions as a primary inhibitor of the adenosine A_2A receptor. Additionally, the study determined that compound 57 satisfied the Rule of Five (Ro5) standards and exhibited robust physicochemical characteristics. The compound exhibited moderate to low levels of hERG inhibition. The conducted investigations highlighted promising outcomes of natural compounds that can orient towards the rational development of effective Parkinson's disease inhibitors.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00305-9.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"17"},"PeriodicalIF":0.0,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multilayered screening for multi-targeted anti-Alzheimer's and anti-Parkinson's agents through structure-based pharmacophore modelling, MCDM, docking, molecular dynamics and DFT: a case study of HDAC4 inhibitors.","authors":"Nikita Chhabra, Balaji Wamanrao Matore, Nisha Lakra, Purusottam Banjare, Anjali Murmu, Arijit Bhattacharya, Shovanlal Gayen, Jagadish Singh, Partha Pratim Roy","doi":"10.1007/s40203-024-00302-4","DOIUrl":"10.1007/s40203-024-00302-4","url":null,"abstract":"<p><strong>Abstract: </strong>Alzheimer's disease (AD) and Parkinson's disease (PD) are neurological conditions that primarily impact the elderly having distinctive traits and some similarities in terms of symptoms and progression. The multifactorial nature of AD and PD encourages exploring potentiality of multi-target therapy for addressing these conditions to conventional, the \"one drug one target\" strategy. This study highlights the searching of potential HDAC4 inhibitors through multiple screening approaches. In this context, structure-based pharmacophore model, ligand profiler mapping and MCDM approaches were performed for target prioritization. Similarly, ligand profiler, MCDM and Docking studies were performed to prioritize multi-targeted HDAC4 inhibitors. These comprehensive approaches unveiled 5 common targets and 5 multi-targeted prioritized compounds consensually. MD simulations, DFT and binding free energy calculations corroborated the stability and robustness of propitious compound 774 across 5 prioritized targets. In conclusion, the screened compound 774 (ChEMBL 4063938) could be a promising multi-targeted therapy for managing AD and PD further rendering experimental validation.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00302-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative analysis of the genomic and expression profiles of ANLN and KDR as prognostic markers in breast Cancer.","authors":"Aamir Mehmood, Rongpei Li, Aman Chandra Kaushik, Dong-Qing Wei","doi":"10.1007/s40203-024-00301-5","DOIUrl":"10.1007/s40203-024-00301-5","url":null,"abstract":"<p><p>Breast cancer (BC) remains a highly heterogeneous disease, complicating diagnosis and treatment. This study investigates the prognostic significance of Anillin (<i>ANLN</i>) and Kinase Insert Domain Receptor (<i>KDR</i>) genes, focusing on their mutational and expression landscapes in BC using data from The Cancer Genome Atlas (TCGA). We found that high <i>ANLN's</i> expression is strongly associated with poor overall survival, highlighting its potential as a robust prognostic marker. In contrast, <i>KDR</i>, despite its higher mutation frequency, showed a less significant correlation with survival outcomes. Machine learning (ML) models incorporating transcriptional and translational data further supported <i>ANLN's</i> prognostic value, demonstrating superior accuracy in survival stage prediction when both genes were analyzed together. Functional enrichment analysis revealed that <i>ANLN</i> is primarily involved in cell cycle regulation, while <i>KDR</i> is linked to angiogenesis, suggesting that combined targeting of these pathways could enhance therapeutic efficacy. These findings underscore the potential of <i>ANLN</i> and <i>KDR</i> as complementary biomarkers in BC prognosis and highlight the need for further validation in diverse cohorts.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00301-5.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into structural and binding studies of pollen allergen Bet v 1 using computational approaches.","authors":"Mansi Pandit, Nandita Narayanasamy, N Latha","doi":"10.1007/s40203-024-00303-3","DOIUrl":"10.1007/s40203-024-00303-3","url":null,"abstract":"<p><p>Bet v 1, the European White Birch tree pollen allergen is responsible for a number of allergic responses in humans such as rhinitis, asthma and oral allergy syndrome. The allergen belongs to pathogenesis-related (PR) class 10 protein superfamily and exists in several naturally occurring isoforms. Limited structural information on Bet v 1 isoallergens and variants prompted us to carry out their in silico structural characterization. In this study, three-dimensional structures of Bet v 1 isoallergens were predicted followed by allergen-antibody docking with Bet v 1- specific human IgE. Further, molecular dynamics simulations were performed for the allergen-antibody complexes. In addition, in silico mutagenesis was carried out for the design of a hypoallergenic variant of Bet v 1. Our study aimed to elucidate the differential ability of Bet v 1 isoallergens in eliciting allergic responses based on structural features and also identified a potential hypoallergen allowing us to propose it as a promising candidate for treating birch pollen-induced allergy.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00303-3.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of potential MMP-8 inhibitors through virtual screening of natural product databases.","authors":"Yi Wang, Xiushan Chen","doi":"10.1007/s40203-024-00299-w","DOIUrl":"https://doi.org/10.1007/s40203-024-00299-w","url":null,"abstract":"<p><p>Matrix metalloproteinase-8 (MMP-8), a type II collagenase, is a key enzyme in the degradation of collagens and is implicated in various pathological processes, making it a promising target for drug discovery. Despite advancements in the development of MMP-8 inhibitors, concerns over potential adverse effects persist. This study aims to address these concerns by focusing on the development of novel compounds with improved safety profiles while maintaining efficacy. In this study, we employed a computational approach to screen potent and safe inhibitors of MMP-8 from the Natural Product Activity and Species Source Database (NPASS). Initially, we constructed a pharmacophore model based on the crystal structure of the MMP-8-FIN complex (PDB ID: 4EY6) utilizing the Pharmit tool. This model then guided the selection of 44 promising molecules from NPASS, setting the stage for further analysis and evaluation. We comprehensively evaluated their drug-likeness and toxicity profiles. Molecules 21, 4, and 44 were identified as potentially effective MMP-8 inhibitors through a robust pipeline that included ADMET profiling, molecular docking, and molecular dynamics simulations. Notably, molecule 21 stood out for its low toxicity, high binding stability, and favorable ADMET profile, while molecule 44 demonstrated excellent affinity. These compounds offer structural novelty compared to known MMP-8 inhibitors. These computational results can be combined with in vitro experiments in the future to validate their activity and safety. These findings provide an important reference for drug design of MMP-8 inhibitors.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico design and computational screening of berberine derivatives for potential antidiabetic activity through allosteric activation of the AMPK pathway.","authors":"Bibhuti Bhusan Kakoti, James H Zothantluanga, Kangkan Deka, Raj Kumar Halder, Dhritiman Roy","doi":"10.1007/s40203-024-00295-0","DOIUrl":"https://doi.org/10.1007/s40203-024-00295-0","url":null,"abstract":"<p><p>Globally, there is an increase in the prevalence of metabolic illnesses, including diabetes mellitus. However, current therapies for diabetes and other metabolic illnesses are not well understood. Pharmacological treatment of type 2 diabetes is challenging, moreover, the majority of antidiabetic medications are incompatible with individuals who have cardiac disease, renal illness, or liver damage. Despite the ongoing development of innovative medicines, the quest for an optimal treatment that serves both as a hypoglycaemic agent and mitigates diabetes-related problems remains unattained. Recent research demonstrates that berberine has significant promise in the treatment of diabetes. Berberine influences glucose metabolism by enhancing insulin secretion, promoting glycolysis, decreasing adipogenesis, disrupting the function of the mitochondria, stimulating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, thereby augmenting glucokinase activity. In this study, we virtually designed and synthesized 5 berberine derivatives (data not yet published) to study their impact on the AMP-activated protein kinase (AMPK) pathway through molecular docking and dynamic simulation study. Activation of AMPK plays an important role by enhancing glucose uptake in cells. Berberine and its derivatives showed potential for allosteric activation of the AMPK pathway. The allosteric activation of AMPK α- & β-subunit involves complex interactions with standard activators like A-769662. Berberine and its derivatives showed potential binding affinity at the allosteric site of AMPK α- & β-subunit, forming similar interactions to A-769662. Molecular dynamic simulations indicated stability of these complexes. However, interactions of these derivatives with the AMPK γ-subunit were less stable, suggesting limited potential for allosteric activation at this site. Further studies are required to assess the long-term stability and efficacy of berberine and its derivatives as allosteric AMPK activators. Additionally, ADMET predictions suggest these derivatives to be safe, warranting further experimental and preclinical investigations as potential antidiabetic agents.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00295-0.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel 3-dehydroquinate dehydratase (DHQD) inhibitors for anti-tuberculosis activity: insights from virtual screening, molecular docking, and dynamics simulations.","authors":"Mustafa Alhaji Isa, Abidemi Paul Kappo","doi":"10.1007/s40203-024-00298-x","DOIUrl":"https://doi.org/10.1007/s40203-024-00298-x","url":null,"abstract":"<p><p>Tuberculosis (TB) remains a pressing global health concern, causing substantial mortality and morbidity despite existing drugs and vaccines. The escalating challenge of drug-resistant TB underscores the critical need for novel medications. This study focuses on the enzyme 3-hydroquinate dehydratase (DHQD) in the shikimate pathway of <i>Mycobacterium tuberculosis</i> (Mtb), essential for Mtb growth. Using an in silico approach, the crystal structure of DHQD complexed with 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) was obtained from the Protein Data Bank. After meticulous preparation, a diverse library of 9699 compounds from Zinc and PubChem databases was subjected to virtual screening, complying with Lipinski's rule of five and compounds capable of binding to DHQD with less binding energy. Molecular docking analysis identified eight compounds with highly favorable binding energies, ranging from -8.99 to -8.39 kcal/mol, surpassing CA's -4.93 kcal/mol. To assess their potential as inhibitors, these eight compounds were subjected to scrutiny for pharmacokinetic properties, encompassing Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) demonstrated desirable pharmacokinetic attributes and were selected for further investigation. Subsequent molecular dynamics (MD) simulations and molecular generalized born surface area (MM-GBSA) analyses were conducted. Molecular dynamics (MD) simulations showed that these five compounds formed stable complexes with DHQD over 50 ns, with root mean square deviation (RMSD) values ranging from 1.57 Å to 2.34 Å, indicating high structural stability. In addition, the MM-GBSA binding energy calculations showed that these compounds had favourable binding affinities, with ZINC14981770 exhibiting the lowest free binding energy of -32.70 kcal/mol, followed by ZINC14741224 at -29.67 kcal/mol and ZINC14743698 at -28.79 kcal/mol. These binding energies significantly outperformed the reference compound CA, which had a binding energy of -10.62 kcal/mol. Based on these findings; these five compounds hold promise as potent inhibitors of Mtb DHQD, pending validation through in vitro and in vivo experiments.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-silico-based lead optimization of hit compounds targeting mitotic kinesin Eg5 for cancer management.","authors":"Damilola S Bodun, Damilola A Omoboyowa, Victor F Olofinlade, Adeyemi O Ayodeji, Andrea Mauri, Uchechukwu C Ogbodo, Toheeb A Balogun","doi":"10.1007/s40203-024-00300-6","DOIUrl":"https://doi.org/10.1007/s40203-024-00300-6","url":null,"abstract":"<p><p>Lead optimization is vital for turning hit compounds into therapeutic drugs. This study builds upon a prior in silico research, where the hit compounds had better binding affinity and stability compared to a reference drug. Using a genetic algorithm, 12,500 analogs of the top compounds from the prior study were generated. Virtual screening was done using a quantitative structure-activity relationship (QSAR) model. Top analogs, selected based on pChembL values below 6.000nM, underwent molecular docking targeting Human Eg5. The top five analogs from this study (Compound 9794, Compound 8592, Compound 9786, Compound 2744, and Compound 3246) demonstrated strong binding energies and interactions with key amino acids (GLU 116, GLU 117, and ARG 119). MMGBSA analysis revealed comparable affinities to the co-crystallized ligand, suggesting the top analogs' potential as Human Eg5 inhibitors. Induced fit docking highlighted Compound 9786's superior efficacy. Quantum Polarized Ligand Docking indicated promising scores for Compounds 8592 and 9786. ADMET predictions offered insights into pharmacological properties, with all compounds predicted to be HIA-positive and non-carcinogenic. Further MD simulation study confirms the stability of the top compounds in the active site of Eg5. This study shows the significance of integrated strategies in drug design. However, in vitro and in vivo studies should be conducted for these promising candidates to confirm their efficacy as Eg5 inhibitors.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00300-6.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"9"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11703796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling structural components of dibenzofuran-based MMP-12 inhibitors: a comparative classification-dependent analysis with molecular docking-based virtual screening and molecular dynamics simulation.","authors":"Jigme Sangay Dorjay Tamang, Suvankar Banerjee, Balaram Ghosh, Sandip Kumar Baidya, Tarun Jha, Nilanjan Adhikari","doi":"10.1007/s40203-024-00296-z","DOIUrl":"https://doi.org/10.1007/s40203-024-00296-z","url":null,"abstract":"<p><p>The implication of matrix metalloproteinase-12 (MMP-12) in various major disorders including cancer, COPD, cardiovascular disorders, and neurological diseases makes it a potential target for drug discovery. Contemplating the significance of MMP-12, a number of MMP-12 inhibitors were designed, synthesized and tested throughout the world but the non-selective nature of most of those molecules can lead to adverse drug interactions. In contradiction, the dibenzofuran (DBF) and dibenzothiophene (DBT) derivatives showed highly potent and selective MMP-12 inhibition. Therefore, to identify the prime molecular and structural attributes that are affecting the MMP-12 inhibitory activity, the linear discriminant analysis (LDA), Bayesian classification, recursive partitioning, and SARpy analysis were performed to extract the prime attributes of these DBFs and DBTs affecting MMP-12 inhibition. These studies suggested that substructures like isopropyl carboxylic acid, 5-methyl furan, 1,2,4-oxadiazole, and DBT moieties can impart moderate to high contribution for MMP-12 inhibition. Importantly, the outcomes of the current studies were also in agreement with our regression-based study performed earlier. Furthermore, the molecular docking-mediated virtual screening of DBT and DBF analogs of the ChEMBL database demonstrated the viability of other DBT and DBF analogs to become potential MMP-12-selective inhibitors. The molecular dynamics (MD) simulation study of hit molecules also showed the potential of the combination of phosphonic acid ZBG and DBF P1' substituent for effective anchoring/binding at the MMP-12 active site. Therefore, the findings may help in the discovery and designing of novel MMP-12 inhibitors that may be used for the treatment of various pathological diseases including cancer and COPD.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00296-z.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11704098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}