In silico pharmacology最新文献

{"title":"The inhibitory effects of <i>Centella asiatica</i> compounds on myeloid cell leukemia 1 (MCL-1) in cancer: a computational study.","authors":"Cecilia Oluwamodupe, Olorunfemi Oyewole Babalola, Paul Olamide Ottu, Erinayo Tolulope Aladeteloye, Elizabeth Temilolaoluwa Mogaji, Elijah Olamide Olumodeji, Victor Richard Adekanle, Olusola Olalekan Elekofehinti","doi":"10.1007/s40203-025-00399-1","DOIUrl":"10.1007/s40203-025-00399-1","url":null,"abstract":"<p><p>Myeloid cell leukemia 1 (MCL-1), a crucial anti-apoptotic member of the B-cell lymphoma 2 (BCL-2) family, has been extensively documented to be overexpressed in a variety of cancers, where it is essential for fostering cancer cell survival and treatment resistance. Elevated levels of MCL-1 have been observed in hematological cancers, such as acute myeloid leukemia and multiple myeloma, as well as in multiple solid tumors. We therefore examined the potential inhibitory effects of <i>Centella asiatica</i> compounds on MCL-1 using a computational drug discovery approach. Molecular docking analyses, including Glide XP (extra precision) were performed to evaluate the binding affinities of the compounds against the prepared crystal structure of MCL-1 (PDB ID: 6FS1) within the Schrödinger Suites. Additionally, the binding free energies of the compounds were computed to assess their thermodynamic stability within the binding pocket. The physicochemical and pharmacokinetic properties of the identified compounds were analyzed based on Lipinski's Rule of Five (RO5), electrostatic potential distribution, and ADME predictions. Predictive models for MCL-1 inhibitors were developed using AutoQSAR to examine the drug-likeness and biological activity of the screened compounds. We found 12 hit compounds, most of which met the RO5 criteria and were in the suggested ADME parameter range. Additionally, the predicted pIC50 values for these compounds were promising, suggesting their potential as MCL-1 inhibitors. The results of this study offer insightful analysis for the rational design of new anticancer treatments aimed at MCL-1.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"111"},"PeriodicalIF":0.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736388","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":"Screening of antihyperglycemic and cytotoxic properties of <i>Ficus racemosa</i> L. Fruit extract.","authors":"Ananta Swargiary, Manita Daimari, Akalesh K Verma","doi":"10.1007/s40203-025-00397-3","DOIUrl":"10.1007/s40203-025-00397-3","url":null,"abstract":"<p><p><i>Ficus racemosa</i> L. is a important medicinal plant in Assam, traditionally used by the Bodo tribe, who consume its fruit extract as a preventive remedy for diabetes. Despite its widespread ethnomedicinal use, scientific studies on <i>F. racemosa</i> remain limited, particularly regarding the isolation and identification of its bioactive antidiabetic constituents. The present study investigated the metal contents, phytocompounds, anti-diabetic, and cytotoxicity properties of <i>F. racemosa</i> fruits extract. The AAS and GC-MS methods were used to analyze the metallic and phytocompounds of the plant. Enzyme inhibition study was carried out following standard protocols. In silico drug-likeness properties of phytocompounds were performed using computer-aided tools. Docking and output visualization were performed in AutoDock vina and Discovery studio. Pharmacophore modeling and structural superimposition were carried out for lead molecules. GC-MS analysis of the <i>F. racemosa</i> fruit extract showed six compounds. The fruit extract was found to contain only trace levels of toxic elements, indicating its safety for therapeutic use. In vitro study showed minimal cytotoxicity of the plant extract. Biochemical enzyme assays showed potential α-amylase and α-glucosidase inhibitory property of <i>F. racemosa</i>. Plant extract showed better enzyme inhibitory property compared to standard inhibitor, acarbose (<i>P</i> ≤ 0.05). All six compounds showed favorable drug-likeness, with compound-3 displaying the strongest binding in docking studies. Pharmacophore features and structure superimposition revealed compound-3 as a pivot molecule. Both the invitro and in silico study revealed similar results showing <i>F. racemosa</i> extract as a strong inhibitor of α-amylase and α-glucosidase. Thus, the present study suggests that the <i>F. racemosa</i> fruits may be a potential source of antihyperglycemic agents.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"110"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736387","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 exploration of pyrocannabinoid interactions with key protein targets.","authors":"Giovanni A Ramirez, Tesfay T Tesfatsion, Monica K Pittiglio, Kyle P Ray, Andrew Westerkamp, Westley Cruces","doi":"10.1007/s40203-025-00391-9","DOIUrl":"10.1007/s40203-025-00391-9","url":null,"abstract":"<p><p>Cannabinoids, particularly those derived from cannabis, attract considerable attention in recent years for their therapeutic potential in treating various diseases and ailments. In this study, we identify cannabinoid byproducts that result from the combustion of cannabidiol-henceforth referred to as pyrocannabinoids-and employ molecular docking simulations to investigate their interactions with key protein targets implicated in different physiological processes. Specifically, we focus on peroxisome proliferator-activated receptor gamma, p21-activated kinase 1, CB1, CB2, and GPR119 proteins, elucidating the binding modes and affinities of pyrocannabinoid byproducts to these receptors. This investigation is done in collaboration with Real Isolates LLC. Our findings reveal diverse ligand-protein interactions, with some pyrocannabinoids displaying favorable binding energies and stable ligand-protein complexes. However, variations in binding affinities across different proteins underscore the complex pharmacological profiles of the pyrocannabinoids. Furthermore, the prediction of adsorption, distribution, metabolism, excretion and toxicity properties highlights both promising and concerning aspects of cannabinoid pharmacokinetics, emphasizing the need for thorough preclinical evaluation. Additionally, our investigation into potential metabolic sites using cytochrome P450 enzymes provides insights into cannabinoid metabolites. Overall, our study contributes to the understanding of pyrocannabinoid pharmacology and informs the rational design of pyrocannabinoid-based therapeutics. Further experimental validation is warranted to translate these findings into clinically relevant applications.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00391-9.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"109"},"PeriodicalIF":0.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736386","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":"Unlocking nature's antidiabetic potential: computer-aided discovery of α-amylase and α-glucosidase inhibitors in <i>Andrographis paniculata</i> leaves.","authors":"Ananta Swargiary, Manita Daimari, Mritunjoy Kumar Roy, Dulur Brahma","doi":"10.1007/s40203-025-00396-4","DOIUrl":"10.1007/s40203-025-00396-4","url":null,"abstract":"<p><p>The study aims to provide <i>in-vitro</i> evidence for the potential inhibition of α-glucosidase and α-amylase enzymes by five selected medicinal plants. The present study investigated the in vitro α-amylase and α-glucosidase inhibitory activity of <i>Andrographis paniculata</i> following standard protocols. GC-MS analysis was carried out to identify the bioactive compounds. Furthermore, molecular docking and MD simulation was carried out to understand the binding affinity of the <i>A. paniculata</i> compounds with the pancreatic enzymes. The crude extracts of plants showed a considerable α-amylase and α-glucosidase inhibitory activity. The IC₅₀ values of α-amylase and α-amylase inhibition was found to be 1.72 ± 0.03 mg/ml and 0.30 ± 0.01 mg/ml, respectively. Refence drug, acarbose also showed almost similar inhibitory activity. Eight probable phytocompounds were identified using GC-MS analysis. Compund-7 showed the strongest binding affinity with both the α-amylase and glucosidase enzymes. MD simulation study observed slightly more stable and compact structure of α-amylase-phytocompound structure compared to acarbose-protein complex. The study suggests that <i>A. paniculata</i> extracts have potential for managing hyperglycemia and type-2 diabetes mellitus. However, further research is required to confirm their efficacy and safety.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00396-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"108"},"PeriodicalIF":0.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736389","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 identification of phytoconstituents from <i>Capparis sepiaria</i> as interleukin-1 inhibitors for rheumatoid arthritis: molecular docking, ADMET profiling, and molecular dynamics simulation.","authors":"Darius R Martin, Antoinette Ajmal, Mervin Meyer, Abram M Madiehe","doi":"10.1007/s40203-025-00386-6","DOIUrl":"10.1007/s40203-025-00386-6","url":null,"abstract":"<p><p>In this study computational methods were used to explore the anti-inflammatory properties of <i>Capparis</i> (<i>C.</i>) <i>sepiaria</i> extracts; focusing on their activity against pro-inflammatory cytokine, interleukin-1 (IL-1). Molecular docking was performed on 18 <i>C. sepiaria</i> phytoconstituents using AutoDock VinaXB. The study identified five compounds (CIDs 8122, 33934, 605626, 638072, 5363269) with high affinity for IL-1. Notably, CID 638072 demonstrated superior binding affinity compared to standard controls such as thalidomide. Pharmacokinetic and toxicity profiles were assessed using SwissADME and pkCSM which showed that all these compounds met acceptable criteria as promising anti-inflammatory agents. Molecular dynamics simulations with GROMACS (version 2019) confirmed the stability and interaction dynamics of these compounds, which support the docking results. The findings validate the traditional medicinal use of <i>C. sepiaria</i> for the treatment of inflammation, suggesting that CID 638072 holds significant potential for further development into a natural anti-inflammatory therapeutic. This research provides clues for the therapeutic applications of <i>C. sepiaria</i>, advancing the search for effective natural remedies for the treatment of inflammation. Further experimental validation is necessary to transition this study from computational predictions to clinical applications.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"106"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692839","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":"Aryl benzoyl hydrazide derivatives as potent inhibitors of the NS2B-NS3 protease and RNA-dependent RNA polymerase of the zika virus.","authors":"R P Yadav, N R Jena","doi":"10.1007/s40203-025-00395-5","DOIUrl":"https://doi.org/10.1007/s40203-025-00395-5","url":null,"abstract":"<p><p>The NS2B-NS3 protease and the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are interlinked with viral genome replication. Therefore, inhibiting their activities would reduce the viral loads in patients. To identify molecules that can strongly bind to the substrate binding site of the NS2B-NS3 protease of the ZIKV, interactions of several aryl benzoyl hydrazide (ABH) derivatives (10b, 10c, 10g, 11p, and 11q) and some anti-influenza drugs (Zanamivir, Laninamivir, Baloxavir, Oseltamivir, Rimantadine, Peramivir, and Amantadine) with the ZIKV NS2B-NS3 protease are studied herein by using combined density functional theoretic, docking, molecular dynamics (100 ns MD simulations), and free-energy methods. Among these molecules, 11q binds strongly to the ZIKV protease with a ΔG_bind of about - 15.70 ± 2.30 kcal/mol. Its binding to the NS2B-NS3 protease is stronger than the anti-influenza drugs studied herein. Notably, the binding affinity of 11q is found to be approximately 4 kcal/mol more negative than that of SYC-1307, a known allosteric inhibitor of the ZIKV protease. 11q is also found to bind to the NTP and allosteric sites of the ZIKV RdRp. However, the binding of 11q to the NTP site of RdRp is preferred over that of the allosteric site. Interestingly, extending the simulation time to 500 ns did not alter the structure of 11q bound to both ZIKV protease and the NTP site of RdRp. However, 11q showed a higher affinity toward the NS2B-NS3 protease than the NTP site of RdRp. Computed ADMET parameters, Lipinski's rule of five, and binding affinities suggest that 11q would be a better drug candidate against ZIKV infections.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00395-5.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"107"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700769","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":"Pharmacophoric analogs of Savolitinib reveal promising inhibitors of the c-MET receptor tyrosine kinase for drug discovery: in silico investigation.","authors":"Lateef Adegboyega Sulaimon, Hameedah Ayanfunke Bamiji, Mercy Eshiet Akpekong, Toyyibat Adelola Asade, Usman Jamila Bashir, Damola Habeeb Adetunji, Ireoluwa Yinka Joel, Rahmat Adetutu Adisa, Titilola Aderonke Samuel, Ashraf Akintayo Akintola","doi":"10.1007/s40203-025-00394-6","DOIUrl":"https://doi.org/10.1007/s40203-025-00394-6","url":null,"abstract":"<p><p>The c-MET receptor tyrosine kinase has become a key focus for therapeutic intervention in various cancer types due to its crucial role in driving cancer progression and metastasis. While Savolitinib, a specific inhibitor of c-MET, has demonstrated promise in clinical trials, its limited availability within the body and the risk of developing resistance have prompted a quest for alternative inhibitors. In this research endeavor, we downloaded and screened a range of pharmacophoric analogs inspired by Savolitinib to explore new avenues for inhibiting c-MET. By delving into the molecular structure of Savolitinib and deciphering how it interacts with the c-MET kinase, we aimed to identify critical structural features and functional groups that could be modified to enhance its inhibitory efficacy and pharmacological properties. Employing computational modeling and pharmacokinetic assessments, this research strives to unveil novel analogs that may exhibit superior potency, selectivity, and overall drug-like attributes. Out of the 997 compounds screened, seventeen demonstrated binding energy values comparable to or greater than - 10.2 kcal/mol obtained for Savolitinib during the redocking experiment. Following a thorough evaluation via in silico ADMETox and drug-likeness prediction, two compounds, namely CID_134565115 and CID_153611202, emerged as promising candidates. They not only exhibited favorable binding energy values but also displayed a well-balanced profile concerning stability, drug-likeness and toxicity. In summary, both CID_134565115 and CID_153611202 demonstrated favorable binding energies and distinctive interaction patterns, surpassing the established Savolitinib. Although our computational study highlights the promising potential of these lead-like candidates in obstructing oncogenic c-MET signaling, further experimental investigations are necessary to verify and establish their preclinical relevance.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"104"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700771","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":"Pharmacokinetic and toxicological profile in pharmaceutical bioprospecting of caryophyllene molecules using computational biology for therapeutic purposes.","authors":"André Nogueira Cardeal Dos Santos, José Ednésio da Cruz Freire, Andrelina Noronha Coelho-de-Souza","doi":"10.1007/s40203-025-00392-8","DOIUrl":"https://doi.org/10.1007/s40203-025-00392-8","url":null,"abstract":"<p><p>β-Caryophyllene, abundant in plants such as <i>Salvia rosmarinus</i>, <i>Cannabis sativa</i>, and <i>Hyptis crenata</i>, possesses various biological activities, including anti-inflammatory, analgesic, neuroprotective, and anticancer properties. However, its high lipophilicity and low stability in hydrophilic environments limit its therapeutic application. To overcome these limitations, the study aimed to bioprospect an molecular derivatives of caryophyllene with improved bioavailability using computational biology analyses. The Canonical SMILES of the molecules were obtained from PubChem and submitted to various servers for analysis of physicochemical, pharmacokinetic, and toxicological properties. Of the 60 identified molecular derivatives, only one met 44 selection criteria, including gastrointestinal absorption, plasma protein binding, metabolism by CYP₄₅₀ enzymes, and toxicological parameters. Comparisons between β-caryophyllene (βC) and caryophyllene-keto-epoxide (CKE) showed that CKE has better gastrointestinal absorption and lower affinity for plasma proteins, increasing the free fraction in the blood. Both compounds do not inhibit nor are they substrates for CYP₄₅₀ enzymes and exhibit good interaction with Caco-2 intestinal cells. CKE, with log P and log D within the desired range, demonstrated to be a more effective alternative in terms of bioavailability compared to βC. These results suggest that CKE can overcome the limitations of βC, offering better stability and bioavailability, thereby enhancing its therapeutic applications. However, further research is necessary to determine whether the primary therapeutic targets of βC remain the same for CKE and to evaluate the differences in therapeutic efficacy between them.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00392-8.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"105"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700770","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":"Oral absorption of semaglutide: pharmacokinetic modeling and molecular dynamics simulations.","authors":"Palak Nitin Agarwal, Ian S Haworth","doi":"10.1007/s40203-025-00393-7","DOIUrl":"10.1007/s40203-025-00393-7","url":null,"abstract":"<p><p>Semaglutide is a GLP-1 receptor agonist that is formulated for oral administration as Rybelsus®. Structurally, semaglutide is a lipid-modified alpha-helical peptide and its absorption, which occurs mainly from the stomach, may be dependent on its conformational properties. Therefore, it is important to include three-dimensional structural parameters that reflect conformation in a pharmacokinetic model of semaglutide. We used pharmacokinetic modeling to simulate the absorption of semaglutide and identify molecular and physiological parameters that may govern this process. A molecular radius of 5.8 Å and a gastric pore radius of 10.25 Å were required to reproduce the observed stomach absorption and plasma concentration vs. time profile of oral semaglutide at a dose of 10 mg. To determine if this molecular radius can be achieved conformationally, molecular dynamics simulations were performed. These simulations showed that the linker-lipid chain of semaglutide wraps around the peptide alpha-helix and produces a helical structure with an average molecular radius (including the peptide, linker and lipid) that falls in the same range as that required in the pharmacokinetic model. Therefore, this linker-lipid wrapping may be necessary for semaglutide to be absorbed into the systemic circulation. This work shows the potential for using molecular modeling in parameterization of pharmacokinetic models for molecules in which conformational variability may influence the pharmacokinetics.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00393-7.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"103"},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677058","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":"Inward opening (IO) to outward opening (OO) 'catalytic transition' and OO to IO 'relaxation' of P-glycoprotein: to investigate the role of helices in efflux through targeted molecular dynamics simulation.","authors":"Pranabesh Mandal, Priyanka Rani, Durg Vijay Singh","doi":"10.1007/s40203-025-00389-3","DOIUrl":"https://doi.org/10.1007/s40203-025-00389-3","url":null,"abstract":"<p><p>P-glycoprotein (P-gp) is a membrane protein that effluxes xenobiotics across cell membranes via ATP hydrolysis. It is overexpressed mainly in cancer cells and is responsible for multidrug resistance by effluxing chemotherapeutic molecules. To unearth the coordinated mechanism and function of different domains i.e., nucleotide binding domain (NBD), transmembrane domain (TMD) and transmembrane helices (TMHs) in catalysis, human P-gp was modelled in Inward Opening (IO) and Outward Opening (OO) states and further subjected to targeted molecular dynamics (tMD) simulations. Structural transition frames between IO ⇌ OO were obtained from the clustering of tMD simulation trajectories. Protein model quality scores (ProSA Z-scores) were evaluated for conformational states. The results showed that the IO → OO transition is an energetically uphill process requiring a major structural transition involving 131 distinct conformational states, coupled with ATP hydrolysis. In contrast, the OO → IO relaxation, crucial for resetting the transporter, does not follow the same transition pathway and is an energetically downhill process involving only 90 states, indicating a faster and distinct mechanism. The helix pairs 1&7 and 6&12 are observed to be relatively static, forming the core of the TMD, while pairs 3&9 and 4&10 are moderately dynamic, and pairs 5&11 and 2&8 are highly dynamic, located more peripherally. The static and dynamic nature and position of these helix pairs justify their respective roles in substrate binding and efflux, and these findings may provide insight into the design and development of next-generation P-gp inhibitors.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00389-3.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 2","pages":"102"},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661416","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}