Journal of Computer-Aided Molecular Design最新文献

{"title":"Deciphering the sequence-dependent unfolding pathways of an RNA pseudoknot with steered molecular dynamics","authors":"Akansha Pandit,&nbsp;Shubham Srivastava,&nbsp;Neeraj Kumar,&nbsp;Devesh M. Sawant","doi":"10.1007/s10822-025-00598-0","DOIUrl":"10.1007/s10822-025-00598-0","url":null,"abstract":"<div><p>Programmed ribosomal frameshifting in Simian retrovirus-1 (SRV-1) is sensitive to the mechanical properties of an RNA pseudoknot. Unravelling these mechanical intricacies via unfolding reveals fundamental insights into their structural dynamics. Using constant velocity steered molecular dynamics (CV-SMD) simulations, we explored the unfolding dynamics and the impact of mutations on the unfolding pathway of the pseudoknot. Except for A28C, A/U to C mutations that disrupt base triples between the loop 2 and stem 1 significantly weaken the pseudoknot and make it more susceptible to unfolding. Complementary mutations in 3 base pairs of the stem region (S1) enhanced its susceptibility to disruption except for Mut5 (S2). We quantitatively assessed the variations in unfolding pathways by analysing the opening of distinct Canonical (WC) and non-canonical (NWC) interactions, force-extension curves, and potential mean force profiles (as a guiding decision for planning mutations). These findings offer a quantified perspective, showcasing the potential of utilizing the unfolding pathways of RNA pseudoknots to explore the programmability of RNA structures. This insight proves valuable for designing RNA-PROTACS and RNA-aptamers, allowing for the assessment and manipulation of their biological folding/unfolding processes.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856473","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}

{"title":"Exploring the anti-diabetic potential of the Vigna sesquipedalis using in vitro, in vivo and computational models","authors":"Hammad Ahmad,&nbsp;Ashraf Ullah Khan,&nbsp;Waqas Alam,&nbsp;Hany W. Darwish,&nbsp;Abdul Saboor Pirzada,&nbsp;Haroon Khan","doi":"10.1007/s10822-025-00591-7","DOIUrl":"10.1007/s10822-025-00591-7","url":null,"abstract":"<div><p><i>Vigna sesquipedalis</i> is traditionally used for the treatment of various disorders including diabetes but without scientific rational. Therefore, the current study was designed to evaluate its anti-diabetic potential. Antioxidant activity was assessed through DPPH and ABTS radical scavenging assays, while α-glucosidase and α-amylase inhibitory activities for anti-diabetic potential. Based on in vitro results, acute toxicity tests were performed, followed by in vivo studies using streptozotocin-induced diabetic model in mice. The ethyl acetate fraction exhibited the highest antioxidant potential, followed by crude extract. The methanolic crude extract showed the strongest in <i>vitro</i> antidiabetic activity. It was also found to be non-toxic up to 2000 mg/kg body weight. In vivo, the crude extract significantly (P &lt; 0.05) improved body weight and displayed significant anti-diabetic effects. Further analysis of liver glycogen, serum insulin, glycosylated hemoglobin, and histopathology supported the extract overall performance. The virtual screening results showed highest binding energy of the Cyanidin-3-0-G (Cyanidin) with the amylase, Daucosterol with the GLP1, and Psoralidin with the Glucosidase. Similarly, MD simulation of the top hits was performed to investigate the dynamic stability and results showed that the ligand–protein system remains stable for during the simulation. The thermodynamic stability of the system was assessed by performing the binding free energy calculation using MM-PBSA/GBSA. The results of the binding free energy calculations showed favorable binding energies ligand–protein system. In short, the results illustrated potential as a pharmaceutical drug for insulin-dependent diabetes mellitus.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835615","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}

{"title":"Synthesis, TD-DFT calculations, molecular docking and ADME studies of new spiro-oxindole derivatives containing 5(4H)-oxazolone as anti-viral and anti-bacterial agents","authors":"N. Madadi Mahani,&nbsp;H. Hamidian,&nbsp;S. Fozooni,&nbsp;M. Salajeghe","doi":"10.1007/s10822-025-00593-5","DOIUrl":"10.1007/s10822-025-00593-5","url":null,"abstract":"<div><p>Spiro pyrrolidine oxindole and oxazolone compounds have been widely used in medicinal chemistry. They can show anti-viral, anti-diabetic, anti-cancer, anti-bacterial, anti-stress, anti-allergic, and anti-inflammatory effects. The 1,3-dipolar cycloaddition reaction, initiated by the in situ formation of an azomethine ylide, serves as a highly effective synthetic approach for constructing pyrrolidine-appended and pyrrolidine-fused heterocycles. Herein, efficient synthesis of 5 new derivatives of spiropyrrolidine oxindole framework of azomethin ylied with 4-arylidine- 5(4H)-oxasolone as dipolarophile via the one-pot multicomponent 1, 3-dipolar cycloaddition is reported. The chemical structures of the newly synthesized analogs were determined through an analysis of their spectroscopic data. In continuation, biological activity and reactivity of derivatives of spirooxindole were evaluated using computational chemistry methods such as molecular docking, and density functional theory. Also, their pharmacokinetic properties were investigated to evaluate the risk of toxicity using SWISS ADME and PKCSM online sites. In the investigation of molecular docking, the interaction of five spirooxindole derivatives with 6W63 proteins (the main protease of COVID-19) and 4EMV (ATP topoisomerase inhibitor) was studied to investigate their anti-viral and anti-bacterial properties.Based on the analysis of docking, derivatives d and e have antiviral activity with 6w63 protein and interaction b molecule with 4emv protein shows more suitable antibacterial activity. Study of reactivity descriptors obtained from quantum mechanical calculations showed that the reactivity of all compounds is almost the same and compound c is substituted by fluorine; with the formula C₂₆H₂₀FN₃O₃ it is more than other compounds. Pharmacokinetic studies showed that all compounds have high digestive and intestinal absorption and low toxicity which is an important parameter for a drug. Molecular docking, ADMET analysis, and TD-DFT analysis are used to assess the drug-likeness of <i>c</i> compound as both antiviral and anti-bacterial agents.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818170","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}

{"title":"Convolidine as potent BACE1 inhibitor for Alzheimer’s disease; in-silico coupled with in-vitro assessment","authors":"Anuroopa G. Nadh,&nbsp;M. Jitha Kunhikrishnan,&nbsp;Vishal Ravi,&nbsp;Krishnapriya Ramakrishnan,&nbsp;Niyas Rehman,&nbsp;Krishna S. B. Adithya,&nbsp;Amjesh Revikumar,&nbsp;P. R. Sudhakaran,&nbsp;Rajesh Raju","doi":"10.1007/s10822-025-00592-6","DOIUrl":"10.1007/s10822-025-00592-6","url":null,"abstract":"<div><p>Alzheimer’s Disease is a chronic progressive neurodegenerative disorder characterized by impaired intellect and cognitive functions. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD) by initiating the amyloid cascade. Despite significant clinical efforts, most BACE1 inhibitors have failed to yield potent pharmacological effects. Our previous study, identified a group of natural compounds with satisfying pharmacological profiles with high affinity to BACE1, out of which the compound, ‘convolidine’ emerged as the most promising candidate based on the in-silico parameters such as docking score, interacting residues, binding energy, drug-likeness, ADMET, and biological activity prediction. The present study focused on the inhibitory potential of convolidine against BACE1 using dynamics simulation followed by protein-protein docking and in-vitro validation. Molecular dynamics simulation demonstrated that the BACE1-convolidine complex remained stable throughout the entire 200 ns simulation period. Also, the results of the post-dynamic docking study showed a reduced substrate affinity of BACE1 to its substrate, APP (Amyloid precursor protein), when BACE1 is bound to convolidine, suggesting compounds inhibitory potential. This in-silico assessment was validated in-vitro using a FRET-based BACE1 activity assay, where the result well aligned with the computational predictions. The findings revealed that convolidine could effectively inhibit BACE1, with an IC50 value of 0.49 µM, providing a solid foundation for its development as a promising therapeutic agent for AD management.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818283","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}

{"title":"From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4","authors":"Vera A. Spanke,&nbsp;Valentin J. Egger-Hoerschinger,&nbsp;Veronika Ruzsanyi,&nbsp;Klaus R. Liedl","doi":"10.1007/s10822-025-00589-1","DOIUrl":"10.1007/s10822-025-00589-1","url":null,"abstract":"<div><p>Cytochrome P450 3A4 (CYP3A4) is a membrane bound monooxygenase. It metabolizes the largest proportion of all orally ingested drugs. Ligands can enter and exit the enzyme through flexible tunnels, which co-determine CYP3A4’s ligand promiscuity. The flexibility can be represented by distinct conformational states of the enzyme. However, previous state definitions relied solely on crystal structures. We employed conventional molecular dynamics (cMD) simulations to sample the conformational space of CYP3A4. Five conformationally different crystal structures embedded in a membrane were simulated for 1 µs each. A Markov state model (MSM) coupled with spectral clustering (Robust Perron Cluster Analysis PCCA +) resulted in three distinct states: Two open conformations and an intermediate conformation. The tunnels inside CYP3A4 were calculated with CAVER3.0. Notably, we observed variations in bottleneck radii compared to those derived from crystallographic data. We want to point out the importance of simulations to characterize the dynamic behaviour. Moreover, we identified a mechanism, in which the membrane supports the opening of a tunnel. Therefore, CYP3A4 must be investigated in its membrane-bound state.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-025-00589-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular docking, dynamics simulations, and in vivo studies of gallic acid in adenine-induced chronic kidney disease: targeting KIM-1 and NGAL","authors":"Momita Rani Baro,&nbsp;Manas Das,&nbsp;Leena Das,&nbsp;Aashis Dutta","doi":"10.1007/s10822-025-00590-8","DOIUrl":"10.1007/s10822-025-00590-8","url":null,"abstract":"<div><p>Gallic acid (GA), a naturally occurring compound with antioxidant, anti-inflammatory, anti-apoptotic, and regenerative properties, has gained attention for its potential protective role against kidney dysfunction and diseases, though its therapeutic efficacy in this context remains underexplored. The primary objective of this study was to explore the therapeutic effects of GA in treating adenine-induced chronic kidney disease (CKD) in male Wistar rats. The study evaluated GA’s therapeutic potential against CKD, along with its pharmacokinetic and drug-likeness properties through a comprehensive analysis. It also assessed GA’s inhibitory effects on key kidney proteins, KIM-1 and NGAL, using gene expression analysis, molecular docking, and molecular dynamics simulations. The results demonstrated a range of positive effects, including significant improvement in adenine-induced kidney damage, as shown by changes in urine and serum markers, as well as oxidative stress biomarkers, following GA treatment. The study revealed that GA effectively suppresses the adenine-induced gene expression of KIM-1 and NGAL. Furthermore, GA adhered to Lipinski’s Rule of Five, and molecular docking analysis indicated strong interactions and low binding energies between GA and the target proteins KIM-1 and NGAL, further supporting its efficacy in targeting these markers. Additionally, 100 ns molecular dynamics simulations showed that gallic acid has a stronger binding affinity for NGAL than for KIM-1, with higher binding energy, stability, and stronger hydrogen bonds, suggesting that it primarily influences NGAL interactions. This study underscores gallic acid’s potential in reducing adenine-induced kidney damage and improving kidney function, with computational evidence supporting its promise as a treatment for CKD.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622121","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}

{"title":"Multi-targeted benzylpiperidine–isatin hybrids: Design, synthesis, biological and in silico evaluation as monoamine oxidases and acetylcholinesterase inhibitors for neurodegenerative disease therapies","authors":"Nikita Negi,&nbsp;Senthil R. Ayyannan,&nbsp;Rati K. P. Tripathi","doi":"10.1007/s10822-025-00588-2","DOIUrl":"10.1007/s10822-025-00588-2","url":null,"abstract":"<p>Neurodegenerative diseases (NDDs) like Alzheimer’s and Parkinson’s, characterized by gradual loss of neuronal structure and function, results in cognitive and motor impairments. These complex disorders involve multiple pathogenic mechanisms, including neurotransmitter imbalances, oxidative stress, and protein misfolding, necessitating multifunctional therapeutic approaches. Piperidine and isatin are valuable scaffolds in drug design due to their favorable pharmacokinetic profiles, ability to cross blood–brain barrier, and ease of modification. This study focuses on design, synthesis, and evaluation of benzylpiperidine–isatin hybrids as dual inhibitors targeting key enzymes implicated in NDDs: monoamine oxidases (MAO-A/B) and acetylcholinesterase (AChE). Strategic hybridization of piperidine and isatin produced novel benzylpiperidine–isatin hybrids, combining pharmacological benefits of both scaffolds. Synthesized hybrids were tested for MAO-A/B and AChE inhibitory effects. <b>15</b> emerged as a lead inhibitor for both MAO-A (IC₅₀ = 0.108 ± 0.004 μM, competitive and reversible) and AChE (IC₅₀ = 0.034 ± 0.002 μM, mixed and reversible), outperforming donepezil in AChE inhibition. <b>4</b> showed significant MAO-B inhibition (IC₅₀ = 0.057 ± 0.001 μM, competitive and reversible). SAR studies identified crucial structural elements for potency and selectivity, while molecular docking revealed key interactions stabilizing the enzyme–inhibitor complexes. MD simulations of lead molecules demonstrate the ligand's suitability for strong and consistent binding to the respective proteins. Lead compounds were non-neurotoxic, exhibited good antioxidant properties, and had favorable in silico ADMET predictions. These findings suggest that benzylpiperidine–isatin hybrids hold promise as multifunctional agents against NDDs, warranting further refinement to enhance their efficacy and safety.</p><p>Multi-target directed ligands (MTDLs): A series of benzylpiperidine–isatin hybrids were designed, synthesized and assessed as multifunctional agents for treating neurodegenerative diseases, focusing on their ability to inhibit both MAO-A/B and AChE. Molecular docking identified crucial enzyme–inhibitor interactions, while computational assessments of molecular properties and ADMET profiles confirmed their drug-like qualities.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143521753","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}

{"title":"Computational investigation to identify multi-targeted anti-hyperglycemic potential of substituted 2-Mercaptobenzimidazole derivatives and synthesis of new α-glucosidase inhibitors","authors":"Tanya Waseem,&nbsp;Muhammad Kazim Zargaham,&nbsp;Madiha Ahmed,&nbsp;Tausif Ahmed Rajput,&nbsp;Adnan Amin,&nbsp;Humaira Nadeem","doi":"10.1007/s10822-025-00587-3","DOIUrl":"10.1007/s10822-025-00587-3","url":null,"abstract":"<div><p>One of the most widespread diseases recognized all over the world is diabetes, accounting for 1.5 million deaths each year. Recent studies have demonstrated benzimidazole derivatives as potential antidiabetic agents. Hence, the present study is focused on designing new derivatives of 2-mercaptobenzimidazole by C-S cross-coupling reaction and are subjected to computational screening to identify the most promising candidate. Molecular docking and MM-GBSA calculations were performed to ascertain the binding potential with different antidiabetic targets, including α-glucosidase, PPaR-γ, DPP-4, and AMPK. We observed somewhat moderate binding interactions of the synthesized compound against the α-glucosidase. Since binding affinities can be improved using synthetic chemistry approaches, synthesis of analogues (A-18a-c) by designing hybrids at sites such as the acidic functionality of A-18 was done. The analogue A-18a, with p-fluorobenzyl substitution, exhibited enhanced binding affinity (-4.339 Kcal/mol) with the α-glucosidase compared to the parent compound (-3.827 Kcal/mol). The synthesized analogues were also subjected to an in-vitro α-glucosidase inhibitory assay. Among them, A-18a exhibited the most significant inhibitory potential, with an IC₅₀ value of 0.521 ± 0.01 µM as compared to the standard drug Acarbose (IC₅₀ 21.0 ± 0.5 µM). This aligns with the computational study findings, where A-18a exhibited stronger binding interactions within the active site of the enzyme. Hence, a promising analogue of the designed compound was synthesized through a computationally guided approach as an anti-hyperglycaemic agent. Additionally, most of the designed compounds showed significantly greater binding affinity with PPaR-γ as compared to the standard pioglitazone. A-18 was successfully synthesized by S-arylation reaction using CuI in 89% yield and was subjected to MD-simulation against PPaR-γ, which revealed stable binding throughout the 200 ns run. Future studies will focus on exploring the activity of the designed drugs against PPaR-γ through in-vitro and in-vivo assays.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div><div><p>Graphical depiction of flow of study starting from drug designing and followed by the prediction of molecular targets, ligand binding and molecular dynamics.</p></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475207","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}

{"title":"Discovering promising drug candidates for Parkinson’s disease: integrating miRNA and DEG analysis with molecular dynamics and MMPBSA","authors":"Bisma Ishtiaq,&nbsp;Rehan Zafar Paracha,&nbsp;Maryum Nisar,&nbsp;Saima Ejaz,&nbsp;Zamir Hussain","doi":"10.1007/s10822-025-00586-4","DOIUrl":"10.1007/s10822-025-00586-4","url":null,"abstract":"<div><p>Parkinson’s disease (PD) is a progressive neurological disorder with an increasing prevalence in aging populations. Identifying effective therapeutic targets and treatments remains a critical challenge. This study aimed to discover potential therapeutic targets and design novel compounds for PD treatment. Gene expression analysis was conducted using diverse datasets, including microarray, mRNA sequencing, and miRNA sequencing. While no common genes were identified across all datasets, the RNA-seq dataset GSE-135036 was prioritized. The investigation focused on downregulated miRNAs targeting upregulated mRNAs, revealing that hsa-mir-5585 regulates Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) within the Shigellosis pathway. Given RIPK1’s role in cell death and inflammation, it emerged as a promising therapeutic target for PD. To identify RIPK1 inhibitors, 67 compounds were screened via molecular docking, with CHEMBL-3109201 exhibiting the highest binding affinity. A structurally similar compound, CHEMBL-76328382, also demonstrated strong interactions. A fragment-based drug design approach generated two novel compounds, BI-1215 and BI-146, which, along with RIPK1-IN-4 and CHEMBL-70909876, were shortlisted based on docking scores and ADME profiles. Molecular dynamics simulations confirmed the stability of CHEMBL-70909876 and BI-1215, with RMSD fluctuations between 0.005 and 0.2 nm. MM-PBSA analysis further validated their superior thermodynamic stability and binding affinity compared to other candidates. This study offers novel insights into PD pathogenesis and potential therapeutic interventions, marking a significant step toward effective treatment strategies for this debilitating disorder.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-025-00586-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico exploration of natural xanthone derivatives as potential inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and cellular entry","authors":"Vincent A. Obakachi,&nbsp;Vaderament-A. Nchiozem-Ngnitedem,&nbsp;Krishna K. Govender,&nbsp;Penny P. Govender","doi":"10.1007/s10822-025-00585-5","DOIUrl":"10.1007/s10822-025-00585-5","url":null,"abstract":"<div><p>The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgent need for effective antiviral therapies, particularly against vaccine-resistant variants. This study investigates natural xanthone derivatives as potential inhibitors of the ACE2 receptor, a critical entry point for the virus. We computationally evaluated 91 xanthone compounds derived from <i>Swertia chirayita</i>, identifying two promising candidates: 8-O-[β-D-Xylopyranosyl-(1→6)-β-D-glucopyranosyl]-1,7-dihydroxy-3-methoxy xanthone (XAN71) and 8-O-[β-D-Xylopyranosyl-(1→6)-β-D-glucopyranosyl]-1-hydroxy-3,7-dimethoxy-xanthone (XAN72). Molecular docking and dynamics simulations (MDDS) were performed to assess their binding energy and stability within the ACE2 active site, comparing them to the reference inhibitor MLN-4067. The top six compounds were selected based on their docking performance, followed by Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations to quantify binding affinities. Additionally, molecular electrostatic potential (MEP) analysis was conducted to visualize electron density regions relevant to binding interactions. Our results demonstrate that XAN71 and XAN72 exhibit superior binding affinities of -70.97 and − 69.85 kcal/mol, respectively, outperforming MLN-4067 (-61.33 kcal/mol). MD simulations revealed stable interactions with key ACE2 residues, primarily through hydrogen bonds and hydrophobic contacts. The Molecular Electrostatic Potential(MEP) analysis further elucidated critical electron density regions that enhance binding stability. This study establishes XAN71 and XAN72 as viable candidates for ACE2 inhibition, providing a structural basis for their development as natural xanthone-based therapeutics against SARS-CoV-2. These findings highlight the potential of targeting ACE2 with natural compounds to combat COVID-19, particularly in light of emerging viral variants.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-025-00585-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}