Journal of Biomolecular Structure & Dynamics最新文献

{"title":"Structural dynamics of influenza A (H1N1) hemagglutinin protein: a comparative study of Indian (2018) isolate with its evolutionary neighbor, Californian (2009) strain.","authors":"Shilpa Sri Pushan, Mahesh Samantaray, Muthukumaran Rajagopalan, Amutha Ramaswamy","doi":"10.1080/07391102.2024.2317985","DOIUrl":"10.1080/07391102.2024.2317985","url":null,"abstract":"<p><p>This work highlights the structure and dynamics of two trimeric HA proteins of the H1N1 virus from different origins, the pandemic Californian (HA_Cal) and its closest Indian neighbor (HA_Ind), reported in 2009 and 2018, respectively. Because of mutation, HA_Ind acquires new N-glycosylation and epitope binding sites along with mutations at RBD, which might trigger an altered viral-host interaction mechanism. Molecular dynamics simulations performed on HA trimers for a period of 250 ns reveal the highly dynamic nature of HA_Cal trimers inherited by the flexibility of HA monomers. In the trimer, the dynamics of one monomer are more pronounced compared to others, and the enhanced dynamics of RBD especially gain attention as they plays a key role during fusion. Conversely, the mutant HA_Ind trimer effectively establishes more H-bond interactions, and accordingly, the trimer undergoes more stabilized dynamics with a relatively lower amplitude of RBD dynamics, as endorsed by the reduced RMSD, Rg, and SASA variations. The cooperative and anti-cooperative motions dissected for the subdomains of both strains also reveal a prominent anticorrelative motion of RBD against other subdomains. In agreement, the free energy landscape of stable HA_Ind is also characterized by a single lowest wide energy basin instead of the two minimum energy basins of the HA_Cal trimer. In essence, the mutant HA_Ind acquires a highly stable conformation with novel functional features, which calls for (i) further investigation on the emerging mutation-mediated variation in viral-host binding mechanism and (ii) the need for further design of site-specific potential inhibitors to face future challenges.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6064-6077"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912700","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":"Noncovalent inhibitors of DprE1 for tuberculosis treatment: design, synthesis, characterization, <i>in vitro</i> and <i>in silico</i> studies of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamides.","authors":"Shivakumar, P Dinesha, D Udayakumar","doi":"10.1080/07391102.2024.2427368","DOIUrl":"10.1080/07391102.2024.2427368","url":null,"abstract":"<p><p>In this study, we present a novel series of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamide derivatives, which exert their inhibitory effect on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) <i>via</i> the establishment of non-covalent interactions with the pivotal Cys387 residue located within the enzyme's active site. These compounds underwent scrutiny for their efficacy in combatting the <i>Mycobacterium tuberculosis</i> H37Rv strain, and compounds T8 and T13 exhibited promising antitubercular activity, boasting a minimal inhibitory concentration (MIC) of 7.99 and 8.27 µM respectively. Additionally, three compounds, T2, T3 and T12, showcased substantial antibacterial activity whereas compounds T12 and T13 exhibited pronounced antifungal efficacy. Remarkably, all active compounds demonstrated negligible cytotoxicity, and none posed harm to normal cells. To attain a more profound comprehension of the attributes of these compounds, we conducted <i>in silico</i> investigations to evaluate their Absorption, Distribution, Metabolism and Excretion properties. Additionally, molecular docking analyses were executed to elucidate their interactions with the DprE1 enzyme. Finally, Density Functional Theory studies were leveraged to explore the electronic characteristics of these compounds, thereby providing insights into their potential utility in the realm of pharmaceuticals.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6351-6365"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638825","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":"Consortium of 'consistent amino acid substitutions' on influenza A (H1N1) viral proteins emerged at specific stages of viral infection: a big data analysis.","authors":"Syeda Lubna, Debashree Bandyopadhyay","doi":"10.1080/07391102.2024.2435056","DOIUrl":"10.1080/07391102.2024.2435056","url":null,"abstract":"<p><p>Influenza A (H1N1) virus has been one of the most common threats to humankind since 1918. The viral genome is frequently substituted, leading to new strains and recurrent pandemics. Despite knowing the effects of single amino acid substitutions on individual viral proteins, the effects of collective substitutions on viral infection remain elusive. Here, we addressed whether the 'consistent amino acid substitutions' occur in a consortium on functional domains and protein-protein interaction (PPI) sites, impacting overall viral infection and host immune responses. By definition, 'consistent substitutions' occur on 'all' the Influenza A (H1N1) viral strains isolated in a particular year. To address this question, big protein data (563370 sequences and 9824 PPI) were analysed using multiple sequence alignment, text mining, protein structure analyses etc. A total of one hundred and five 'consistent substitutions' were mapped on the ten viral proteins of influenza A(H1N1) pdm09 strain. Fifty of those emerged on viral protein functional domains and PPIs, engaged in the specific stages of the viral infection, namely, i) cell surface entry and exit, ii) nuclear import, vRNP assembly, and nuclear export, and iii) antagonizing immune responses. For the first time, the study showed that a consortium of 'consistent substitutions' emerged on protein functional domains and PPIs, impacting specific stages of viral infection rather than a single protein and presumably navigating viral escape from human immune response.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6337-6350"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769431","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":"Machine learning-aided identification of natural compounds targeting Marburg virus VP40 with potential antiviral activity.","authors":"Ahmed M Hassan, Leena H Bajrai, Mai M El-Daly, Thamir A Alandijany, Hattan S Gattan, Isra M Alsaady, Arwa A Faizo, Vivek Dhar Dwivedi, Esam I Azhar","doi":"10.1080/07391102.2024.2435634","DOIUrl":"10.1080/07391102.2024.2435634","url":null,"abstract":"<p><p>Marburg virus infection poses a significant threat to humans due to its high fatality rate. The application of in-silico drug design to target the essential protein target of the virus has been proven to be a fundamental technique to inhibit viral growth. Here, VP40 (a matrix protein) was used as an essential protein target of Marburg, and 2569 natural compounds were screened using the molecular docking and neural network-based DeepPurpose architecture. The top 138 compounds that exhibited a binding score of -8 kcal/mol in molecular docking were used in the best DeepPurpose model to predict the IC50. The best model in DeepPurpose was composed of Morgan and CNN-based encoding for protein and ligand, respectively. The top three compounds, NPL130 (CHEMBL2087156), NPL313 (CHEMBL76073), and NPL371 (CHEMBL54440), were selected from the machine learning model, and molecular dynamics simulation was performed for their best complex along with the control compound complex, Nilotinib (CHEMBL255863). Protein showed less than 0.3 nm of deviation in the complex formed with control and NPL130 compounds. Control had shown the best average MM/GBSA binding energy of -36.97 kcal/mol with the lowest standard deviation of 1.86. A stable complex was indicated by the negative binding free energies of -20 to -25 kcal/mol for all three hits. The free energy landscape showed that, along with the control compound, NPL130 had the biggest conformational space with the lowest free energy. Overall, this study proposed NPL130 as a potential hit compound to target Marburg viral growth.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6402-6418"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769436","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":"<i>In vitro</i>, <i>in silico</i>, and STD-NMR studies of flavonoids from <i>Hypericum helianthemoides</i> (Spach) Boiss. against <i>Leishmania major</i> pteridine reductase 1 (<i>Lm</i>PTR1).","authors":"Salar Hafez Ghoran, Muhammad Yousuf, Humaira Zafar, Muhammad Ikhlas Abdjan, Seyed Abdulmajid Ayatollahi, Atia-Tul-Wahab, Nanik Siti Aminah, Alfinda Novi Kristanti, Aziz-Ur-Rehman, M Iqbal Choudhary","doi":"10.1080/07391102.2024.2435621","DOIUrl":"10.1080/07391102.2024.2435621","url":null,"abstract":"<p><p>Apigenin (<b>1</b>) and 3I,8II-biapigenin (<b>2</b>), a dimer of apigenin, were isolated from the aerial parts of <i>Hypericum helianthemoides</i> (Spach) Boiss. (Hypericaceae family). This study aimed to evaluate the <i>in vitro</i> inhibitory effects of flavonoids <b>1</b> and <b>2</b> against <i>Leishmania major</i> pteridine reductase-1 (<i>Lm</i>PTR1), an essential enzyme for the growth of <i>Leishmania</i> parasites and other trypanosomatid protozoa. The second objective was to understand the binding interactions and structural properties of <i>Lm</i>PTR1 inhibition at the atomic level through extensive <i>in silico</i> analyses and Saturation-Transfer Difference (STD)-NMR studies. Anti-<i>Lm</i>PTR1 results showed that the dimeric form (<b>2</b>) was active (IC₅₀ of 34.65 μM), while the monomeric form (<b>1</b>) was inactive. Computational analyses yielded a grid score of -52.14 kcal/mol and a free energy binding score of -38.23 kcal/mol. A stable ligand-receptor complex at the <i>Lm</i>PTR1 binding site was observed for <b>2</b>. Moreover, several important binding residues in the catalytic triad (Y194 and K198) and the substrate loop (L226, S227, S229, V230, and M233) interacted with <b>2</b>. The STD-NMR results corroborated the computational simulations, indicating that H-6I and H-6II of the conjugated ring system on the biapigenin structure showed the highest interaction with the <i>Lm</i>PTR1 active site. MTT assay results for <b>2</b> against human normal fibroblast cells (BJ cells) exhibited no cytotoxicity at concentrations of 50 and 100 μM. Overall, 3I,8II-biapigenin (<b>2</b>) displayed promise as a candidate for <i>in vivo</i> studies and anti-leishmanial drug development. Further evaluation of the anti-leishmanial and anti-<i>Lm</i>PTR1 activities of bioflavonoid <b>2</b>, along with its analogues, is warranted.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6366-6380"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537196","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":"Targeting dual substrate pockets of colistin resistance conferring MCR-1 of <i>Escherichia coli</i> with natural products: insights from high throughput virtual screening and molecular dynamics simulations.","authors":"Sathish Kumar Marimuthu, Vigneshwar Ramakrishnan, Subbiah Thamotharan","doi":"10.1080/07391102.2024.2445158","DOIUrl":"https://doi.org/10.1080/07391102.2024.2445158","url":null,"abstract":"<p><p>Most Gram-negative multidrug-resistant bacterial infections, including those caused by <i>E. coli,</i> are treated with the last-line drug colistin. Resistance to colistin is primarily developed through the plasmid-mediated <i>mcr-1</i> gene. MCR-1 is a zinc-dependent metalloprotein with two substrate binding sites: one for ethanolamine and another for lipid A. The two binding sites are approximately 12 Å apart. In this work, we explored the potential of natural compounds as inhibitors of MCR-1 activity using high-throughput virtual screening. Potential inhibitor candidates were selected on clustering of the top-scoring compounds and further validation by molecular dynamics simulations. Based on the binding scores and stability in MD simulations, the findings suggest three potential compounds (CNP0334463, CNP0338640, and CNP0239461) that can bind to MCR-1 straddling the two substrate pockets. These molecules belong to the chemical classes of organooxygen as well as benzene and substituted derivatives. The identified dual-site inhibitors have a higher affinity than those binding to individual substrate sites. Representative structures identified from the Gibbs free energy surface, based on the first two principal components, reveal a conformational switch between loop and β-sheet in functionally important regions. The dynamic cross-correlation matrix plot showed correlated and anti-correlated motions related to the conformational switch, zinc ion binding, and inhibitors occupying dual sites. Taken together, our results indicate that the design of dual-site inhibitors may be a novel approach to inhibit MCR-1 activity.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":"43 13","pages":"7139-7154"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185978","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":"Biochemical and <i>in silico</i> analysis of the binding mode of erastin with tubulin.","authors":"Gudapureddy Radha, Pratyush Pragyandipta, Pradeep Kumar Naik, Manu Lopus","doi":"10.1080/07391102.2024.2317984","DOIUrl":"10.1080/07391102.2024.2317984","url":null,"abstract":"<p><p>Erastin (ERN) is a small molecule that induces different forms of cell death. For example, it has been reported to induce ferroptosis by disrupting tubulin subunits that maintain the voltage-dependent anion channels (VDACs) of mitochondria. Although its possible binding to tubulin has been suggested, the fine details of the interaction between ERN and tubulin are poorly understood. Using a combination of biochemical, cell-model and <i>in silico</i> approaches, we elucidate the interactions of ERN with tubulin and their biological manifestations. After confirming ERN's antiproliferative efficacy (IC₅₀, 20 ± 3.2 M) and induction of cell death in the breast cancer cell line MDA-MB-231, the binding interactions of ERN with tubulin were examined. ERN bound to tubulin in a concentration-dependent manner, disorganizing the structural integrity of the protein, as substantiated <i>via</i> the tryptophan-quenching assay and the aniline-naphthalene sulfonate binding assay, respectively. <i>In silico</i> studies based on molecular docking revealed a docking score of -5.863 kcal/mol, suggesting strong binding interactions of ERN with tubulin. Additionally, molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analyses evinced the binding free energy (ΔG_binding) of -31.235 kcal/mol, substantiating strong binding affinity of ERN with tubulin. Ligplot analysis showed hydrogen bonding with specific amino acids (Asn A226, Thr A223, Gln B247 and Val B355). QikProp-based ADME (absorption, distribution, metabolism and excretion) assessment showed considerable therapeutic potential for ERN.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6522-6529"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905722","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":"Cytotoxic monastrol derivatives as adjective inhibitors of drug-resistant Eg5: a molecular dynamics perspective.","authors":"S Shahabipour, A N Shamkhali, N Razzaghi-Asl","doi":"10.1080/07391102.2024.2326195","DOIUrl":"10.1080/07391102.2024.2326195","url":null,"abstract":"<p><p>The mitotic kinesin Eg5 is a motor protein involved in the formation of bipolar spindle and cell division. Eg5 is overexpressed in various cancer cells and Eg5 targeting agents are promising candidates for cancer therapy. Subsequent to the discovery of monastrol as a small-molecule Eg5 modulator, numerous inhibitors/modulators have been reported from which a few entered clinical trials. Mutagenic investigations specified declined sensitivity of Eg5 allosteric site to monastrol due to the occurrence of drug-resistant mutations in some cell cultures. Accordingly, identification of tight binders to the mutant Eg5 allosteric site is an invaluable strategy to devise more efficient Eg5 modulators. We have previously synthesized a few dihydropyrimidinethione (DHPMT)-based 5-carboxamide monastrol derivatives (<b>1</b>-<b>5</b>) with higher cytotoxicities against AGS (IC₅₀ 9.90-98.48 µM) and MCF-7 (IC₅₀ 15.20-149.13 µM) cancer cell lines than monastrol. Within a current study, a structural insight was offered into the binding mechanism of intended derivatives inside the mutant Eg5 loop5/α2/α3 allosteric pocket. Molecular docking of the DHPMT <i>R</i> and <i>S</i>-enantiomers unraveled top-scored Eg5 complexes. Molecular dynamics (MD) simulations were carried out on 5 superior complexes as (<i>R)</i>-<b>2</b>/D130V-Eg5, (<i>R)</i>-<b>4</b>/D130V-Eg5, (<i>R)</i>-<b>5</b>/D130V-Eg5, (<i>R)</i>-<b>5</b>/L214I-Eg5, (<i>R)</i>-<b>5</b>/R119L-Eg5, and the control groups monastrol/D130V-Eg5, monastrol/L214I-Eg5, monastrol/R119L-Eg5. Free energy calculations were conducted through conformational sampling of MD-driven binding trajectories. Our results provided structural details on probable interaction mechanism of the cytotoxic DHPMTs that are difficult to address experimentally. The outputs of the current study propose new monastrol derivatives as probable resistance-overwhelming Eg5 modulators.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6896-6909"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049582","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":"Prediction of SHP2-E76K binding sites based on molecular dynamics simulation and Markov algorithm.","authors":"Si-Pei Zhang, Li-Juan Chen, Zhen-Liang Shi, Xin Li, Ying Ma","doi":"10.1080/07391102.2024.2431193","DOIUrl":"10.1080/07391102.2024.2431193","url":null,"abstract":"<p><p>SHP2-E76K, a mutant encoded by the PTPN11 gene, was associated with various solid tumors, such as lung cancer, glioblastoma, and intellectual disability. SHP2-E76K has become potential drug targets, while there was no effective inhibitor against the mutant currently. At present, the crystal complex structure of SHP099 with SHP2-E76K has been reported in the RCSB PDB protein data bank, however, the dynamic structure of SHP099 binding to the active center of SHP2-E76K protein was still lacking. Therefore, this study used molecular dynamics simulation and Markov model to characterize the kinetics of the inhibitor SHP099 with SHP2-E76K enzyme and to determine the active binding site, which would give a hint of a vital enzyme-substrate interaction in atomistic detail that proposed the potential to be applied for the discovery of more effective SHP2-E76K inhibitors and, in broader terms, dynamic protein-drug interactions.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"7084-7095"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668152","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 study of the piperidine and FtsZ interaction in <i>Salmonella</i> Typhi: implications for disrupting cell division machinery.","authors":"Hithesh Kumar, Anand Manoharan, Anand Anbarasu, Sudha Ramaiah","doi":"10.1080/07391102.2024.2314272","DOIUrl":"10.1080/07391102.2024.2314272","url":null,"abstract":"<p><p>FtsZ, a bacterial cell division protein, is essential for assembling the contractile Z-ring crucial in bacterial cytokinesis. Consequently, inhibiting FtsZ could impede proto-filaments, disrupting FtsZ and other associated proteins vital for cell division machinery. Conduct an <i>in-silico</i> drug interaction study to identify novel drug candidates that inhibit the FtsZ protein, aiming to prevent Multi-Drug Resistant (MDR) <i>Salmonella</i> Typhi. Data mining was performed based on piperidine compounds, which were subsequently screened for safe pharmacokinetic profiles. Compounds that met favorable drug-likeness criteria underwent virtual screening against the FtsZ drug target. Two compounds were chosen for molecular docking and molecular dynamic simulation to verify the binding affinity and stability between the target protein and the potential compounds. The 400 isoforms of piperidine analogues were curated, among them potent compound ZINC000000005416 found to possess high binding affinity (-8.49 kcal/mol) and low dissociation constant (0.597 µM). The highest binding affinity shown by ZINC000000005416 was validated by hydrogen bonds, hydrophobic interaction, and salt bridges with the functional domain of the cell division regulatory protein. Docking profiles, when correlated with molecular dynamic simulation (MDS) depicted stable trajectories and compatible conformational changes in the FtsZ-ZINC000000005416 complex. The stable simulated trajectories were validated through free-energy calculations using the Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) module. Low energy conformations, although the simulation trajectory confirmed the stable ZINC000000005416-FtsZ interaction, which encouraged experimental validations. This study encourages further exploration of the compound ZINC000000005416 as a drug candidate inhibiting FtsZ protein against MDR <i>Salmonella</i> Typhi.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"5886-5899"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697591","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}