{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:14:07Z","timestamp":1790878447280,"version":"4.1.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Human Immunodeficiency Virus type 1 protease (HIV-1 PR) is one of the most challenging targets of antiretroviral therapy used in the treatment of AIDS-infected people. The performance of protease inhibitors (PIs) is limited by the development of protease mutations that can promote resistance to the treatment. The current study was carried out using statistics and bioinformatics tools. A series of thirty-three compounds with known enzymatic inhibitory activities against HIV-1 protease was used in this paper to build a mathematical model relating the structure to the biological activity. These compounds were designed by software; their descriptors were computed using various tools, such as Gaussian, Chem3D, ChemSketch and MarvinSketch. Computational methods generated the best model based on its statistical parameters. The model\u2019s applicability domain (AD) was elaborated. Furthermore, one compound has been proposed as efficient against HIV-1 protease with comparable biological activity to the existing ones; this drug candidate was evaluated using ADMET properties and Lipinski\u2019s rule. Molecular Docking performed on Wild Type, and Mutant Type HIV-1 proteases allowed the investigation of the interaction types displayed between the proteases and the ligands, Darunavir (DRV) and the new drug (ND). Molecular dynamics simulation was also used in order to investigate the complexes\u2019 stability allowing a comparative study on the performance of both ligands (DRV &amp; ND). Our study suggested that the new molecule showed comparable results to that of darunavir and maybe used for further experimental studies. Our study may also be used as pipeline to search and design new potential inhibitors of HIV-1 proteases.<\/jats:p>","DOI":"10.1371\/journal.pone.0284539","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T17:48:17Z","timestamp":1682012897000},"page":"e0284539","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Towards designing of a potential new HIV-1 protease inhibitor using QSAR study in combination with Molecular docking and Molecular dynamics simulations"],"prefix":"10.1371","volume":"18","author":[{"given":"Mouna","family":"Baassi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Moussaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatim","family":"Soufi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-2654","authenticated-orcid":true,"given":"Sanchaita","family":"Rajkhowa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwani","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subrata","family":"Sinha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said","family":"Belaaouad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"issue":"6038","key":"pone.0284539.ref001","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1126\/science.1206399","article-title":"Turning the tide against HIV","volume":"333","author":"R. J. Shattock","year":"2011","journal-title":"Science (80-.)"},{"key":"pone.0284539.ref002","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jmgm.2017.06.007","article-title":"Drug Resistance Mechanism of L10F, L10F\/N88S and L90M mutations in CRF01_AE HIV-1 protease: Molecular dynamics simulations and binding free energy calculations","volume":"75","author":"C. S. Vasavi","year":"2017","journal-title":"J. Mol. Graph. Model"},{"issue":"9740","key":"pone.0284539.ref003","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S0140-6736(10)60936-1","article-title":"Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: A population-based study","volume":"376","author":"J. S. Montaner","year":"2010","journal-title":"Lancet"},{"issue":"1","key":"pone.0284539.ref004","doi-asserted-by":"crossref","first-page":"17","DOI":"10.7326\/0003-4819-135-1-200107030-00005","article-title":"Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease","volume":"135","author":"E. L. Murphy","year":"2001","journal-title":"Ann. Intern. Med"},{"issue":"9513","key":"pone.0284539.ref005","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0140-6736(06)68337-2","article-title":"Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: Comparison between low-income and high-income countries","volume":"367","author":"M. Egger","year":"2006","journal-title":"Lancet"},{"issue":"1","key":"pone.0284539.ref006","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.antiviral.2009.10.007","article-title":"Current status and challenges of antiretroviral research and therapy","volume":"85","author":"J. A. Est\u00e9","year":"2010","journal-title":"Antiviral Res"},{"issue":"7","key":"pone.0284539.ref007","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1021\/acs.jmedchem.5b00497","article-title":"Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends","volume":"59","author":"P. Zhan","year":"2016","journal-title":"J. Med. Chem"},{"issue":"2","key":"pone.0284539.ref008","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1046\/j.1468-1293.2001.00063.x","article-title":"Principles and practice of HIV-protease inhibitor pharmacoenhancement","volume":"2","author":"G. J. Moyle","year":"2001","journal-title":"HIV Med"},{"issue":"11","key":"pone.0284539.ref009","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.3390\/v2112509","article-title":"Molecular basis for drug resistance in HIV-1 protease","volume":"2","author":"A. Ali","year":"2010","journal-title":"Viruses"},{"issue":"3","key":"pone.0284539.ref010","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1080\/07391102.2021.2016486","article-title":"Revealing the drug resistance mechanism of saquinavir due to G48V and V82F mutations in subtype CRF01_AE HIV-1 protease: molecular dynamics simulation and binding free energy calculations","volume":"41","author":"V. C S","year":"2023","journal-title":"J. Biomol. Struct. Dyn"},{"issue":"10","key":"pone.0284539.ref011","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.1080\/07391102.2018.1492459","article-title":"Exploring the drug resistance mechanism of active site, non-active site mutations and their cooperative effects in CRF01_AE HIV-1 protease: molecular dynamics simulations and free energy calculations","volume":"37","author":"V. C.S","year":"2019","journal-title":"J. Biomol. Struct. Dyn"},{"issue":"7","key":"pone.0284539.ref012","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1111\/febs.12743","article-title":"Thermodynamic and structural analysis of HIV protease resistance to darunavir\u2014Analysis of heavily mutated patient-derived HIV-1 proteases","volume":"281","author":"M. Ko\u017e\u00ed\u0161ek","year":"2014","journal-title":"FEBS J"},{"issue":"1","key":"pone.0284539.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0087520","article-title":"New insights into the in silico prediction of HIV protease resistance to nelfinavir","volume":"9","author":"D. A. Antunes","year":"2014","journal-title":"PLoS One"},{"issue":"12","key":"pone.0284539.ref014","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1016\/j.bmcl.2019.03.049","article-title":"Synthesis and biological evaluation of new HIV-1 protease inhibitors with purine bases as P2-ligands","volume":"29","author":"M. Zhu","year":"2019","journal-title":"Bioorganic Med. Chem. Lett"},{"issue":"13","key":"pone.0284539.ref015","doi-asserted-by":"crossref","first-page":"4432","DOI":"10.1021\/jm048972v","article-title":"Unveiling the full potential of flexible receptor docking using multiple crystallographic structures","volume":"48","author":"X. Barril","year":"2005","journal-title":"J. Med. Chem"},{"issue":"27","key":"pone.0284539.ref016","doi-asserted-by":"crossref","first-page":"4455","DOI":"10.2174\/1381612819666131118165824","article-title":"DFT Based QSAR\/QSPR Models in the Development of Novel Anti-tuberculosis Drugs Targeting Mycobacterium tuberculosis","volume":"20","author":"S. Rajkhowa","year":"2014","journal-title":"Curr. Pharm. Des"},{"issue":"8","key":"pone.0284539.ref017","doi-asserted-by":"crossref","first-page":"590","DOI":"10.2174\/1386207311316080002","article-title":"Quantitative Structure-Activity Relationships of the Antimalarial Agent Artemisinin and Some of its Derivatives\u2013A DFT Approach","volume":"16","author":"S. Rajkhowa","year":"2013","journal-title":"Comb. Chem. High Throughput Screen"},{"issue":"5","key":"pone.0284539.ref018","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/1521-3838(200012)19:5<475::AID-QSAR475>3.0.CO;2-3","article-title":"QSAR study of antimalarial activities and artemisinin-heme binding properties obtained from docking calculations","volume":"19","author":"S. Tonmunphean","year":"2000","journal-title":"Quant. Struct. Relationships"},{"issue":"11","key":"pone.0284539.ref019","doi-asserted-by":"crossref","first-page":"5172","DOI":"10.1021\/acs.jmedchem.5b01697","article-title":"Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV\/AIDS","volume":"59","author":"A. K. Ghosh","year":"2016","journal-title":"J. Med. Chem"},{"issue":"5","key":"pone.0284539.ref020","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1086\/590943","article-title":"Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: A systematic review of clinical trials","volume":"47","author":"R. Gupta","year":"2008","journal-title":"Clin. Infect. Dis"},{"issue":"24","key":"pone.0284539.ref021","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1001\/jama.279.24.1977","article-title":"Public health implications of antiretroviral therapy and HIV drug resistance","volume":"279","author":"M. A. Wainberg","year":"1998","journal-title":"J. Am. Med. Assoc"},{"issue":"22","key":"pone.0284539.ref022","doi-asserted-by":"crossref","first-page":"11961","DOI":"10.1128\/JVI.00967-10","article-title":"In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors","volume":"84","author":"Y. Koh","year":"2010","journal-title":"J. Virol"},{"key":"pone.0284539.ref023","author":"K. Roy","year":"2015","journal-title":"Selected Statistical Methods in QSAR"},{"key":"pone.0284539.ref024","first-page":"4","article-title":"COMPUTER AIDED SELECTION IN DESIGN PROCESSES WITH MULTIVARIATE STATISTICS measured by correlations, and maximizes the signal, an iterative algorithm. The technique begins by finding a maximized","volume":"4","author":"A. Paris","year":"2009","journal-title":"Next it is find the second direction along previous sele"},{"issue":"6\u20137","key":"pone.0284539.ref025","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/minf.201000061","article-title":"Best practices for QSAR model development, validation, and exploitation","volume":"29","author":"A. Tropsha","year":"2010","journal-title":"Mol. Inform"},{"issue":"6","key":"pone.0284539.ref026","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.jtusci.2015.04.007","article-title":"QSPR studies of 9-aniliioacridine derivatives for their DNA drug binding properties based on density functional theory using statistical methods: Model, validation and influencing factors","volume":"10","author":"S. Chtita","year":"2016","journal-title":"J. Taibah Univ. Sci"},{"issue":"1","key":"pone.0284539.ref027","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ejps.2012.05.009","article-title":"QSAR, docking and in vivo studies for immunomodulatory activity of isolated triterpenoids from Eucalyptus tereticornis and Gentiana kurroo","volume":"47","author":"A. Maurya","year":"2012","journal-title":"Eur. J. Pharm. Sci"},{"issue":"100 mL","key":"pone.0284539.ref028","first-page":"1","article-title":"Drug Solubility: Importance and Enhancement Techniques","volume":"2012","author":"K. T. Savjani","year":"2012","journal-title":"ISRN Pharm"},{"issue":"1","key":"pone.0284539.ref029","first-page":"256","article-title":"Quantitative structure-toxicity relationship studies of aromatic aldehydes to Tetrahymena pyriformis based on electronic and topological descriptors","volume":"9","author":"A. Ousaa","year":"2018","journal-title":"J. Mater. Environ. Sci"},{"issue":"1","key":"pone.0284539.ref030","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1166\/jbns.2018.1505","article-title":"Molecular docking studies and ADMET properties of new 1.2.3 triazole derivatives for anti-breast cancer activity","volume":"12","author":"M. Ouassaf","year":"2018","journal-title":"J. Bionanoscience"},{"issue":"5","key":"pone.0284539.ref031","doi-asserted-by":"crossref","first-page":"404","DOI":"10.6026\/97320630016404","article-title":"Molecular docking analysis of N-substituted oseltamivir derivatives with the SARS-Cov-2 main protease","volume":"16","author":"M. B.","year":"2020","journal-title":"Bioinformation"},{"issue":"3","key":"pone.0284539.ref032","first-page":"153","article-title":"The zero effect","volume":"195","author":"R. Fortmeyer","year":"2007","journal-title":"Archit. Rec"},{"issue":"9","key":"pone.0284539.ref033","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"D. E. V. Pires","year":"2015","journal-title":"J. Med. Chem"},{"issue":"January","key":"pone.0284539.ref034","first-page":"1","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"A. Daina","year":"2017","journal-title":"Sci. Rep"},{"issue":"SUPPL.","key":"pone.0284539.ref035","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2012.09.019","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"64","author":"C. A. Lipinski","year":"2012","journal-title":"Adv. Drug Deliv. Rev"},{"issue":"12","key":"pone.0284539.ref036","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular properties that influence the oral bioavailability of drug candidates","volume":"45","author":"D. F. Veber","year":"2002","journal-title":"J. Med. Chem"},{"key":"pone.0284539.ref037","doi-asserted-by":"crossref","first-page":"131066","DOI":"10.1016\/j.molstruc.2021.131066","article-title":"Pharmacophore screening, molecular docking, ADMET prediction and MD simulations for identification of ALK and MEK potential dual inhibitors","volume":"1245","author":"H. Zhang","year":"2021","journal-title":"J. Mol. Struct"},{"issue":"6","key":"pone.0284539.ref038","doi-asserted-by":"crossref","first-page":"100082","DOI":"10.1016\/j.jics.2021.100082","article-title":"Multiple QSAR and molecular modelling for identification of potent human adenovirus inhibitors","volume":"98","author":"S. N. Mali","year":"2021","journal-title":"J. Indian Chem. Soc"},{"issue":"12","key":"pone.0284539.ref039","doi-asserted-by":"crossref","DOI":"10.1002\/slct.202103938","article-title":"Elucidating the Interaction and Stability of Withanone and Withaferin\u2010A with Human Serum Albumin, Lysozyme and Hemoglobin Using Computational Biophysical Modeling","volume":"7","author":"S. Rajkhowa","year":"2022","journal-title":"ChemistrySelect"},{"issue":"1","key":"pone.0284539.ref040","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1248\/cpb.55.44","article-title":"QSAR Studies on chalcones and flavonoids as anti-tuberculosis agents using genetic function approximation (GFA) method","volume":"55","author":"P. M. Sivakumar","year":"2007","journal-title":"Chem. Pharm. Bull"},{"issue":"3","key":"pone.0284539.ref041","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.jscs.2012.07.019","article-title":"QSAR modeling of antimalarial activity of urea derivatives using genetic algorithm-multiple linear regressions","volume":"20","author":"A. Beheshti","year":"2016","journal-title":"J. Saudi Chem. Soc"},{"issue":"January","key":"pone.0284539.ref042","first-page":"2","author":"A. Linear","year":"2016","journal-title":"Quantitative Structure-Activity Relationship Analysis of the Anti- tyrosine Activity of Some Tetraketone and Benzyl-benzoate Derivatives Based on Genetic Quantitative Structure-Activity Relationship Analysis of the Anti- tyrosine Activity of Some Tetraket"},{"key":"pone.0284539.ref043","unstructured":"Q. Christoph, M. Meringer, M. Biometry, M. Informatics, and M. Chemistry, \"of Random Pseudomodels By Calculation Rather Than By Tedious Multiple Simulations on Random Number Variables.,\" pp. 1\u201342, 2007."},{"issue":"3","key":"pone.0284539.ref044","first-page":"135","article-title":"Investigation of 5,6-dihydro-2-pyrones derivatives as potent anti-HIV agents inhibitors","volume":"5","author":"E. I. Edache","year":"2015","journal-title":"J. Comput. Methods Mol. Des. Sch. Res. Libr"},{"issue":"4","key":"pone.0284539.ref045","first-page":"709","article-title":"Computational studies on \u03b1-aminoacetamide derivatives with anticonvulsant activities","volume":"7","author":"O. Adedirin","year":"2018","journal-title":"Beni-Suef Univ. J. Basic Appl. Sci"},{"issue":"12","key":"pone.0284539.ref046","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1517\/17460441.2.12.1567","article-title":"On some aspects of validation of predictive quantitative structure-activity relationship models","volume":"2","author":"K. Roy","year":"2007","journal-title":"Expert Opin. Drug Discov"},{"issue":"2","key":"pone.0284539.ref047","doi-asserted-by":"crossref","first-page":"101352","DOI":"10.1016\/j.jksus.2021.101352","article-title":"Combined docking methods and molecular dynamics to identify effective antiviral 2, 5-diaminobenzophenonederivatives against SARS-CoV-2","volume":"33","author":"M. Ouassaf","year":"2021","journal-title":"J. King Saud Univ"},{"issue":"2","key":"pone.0284539.ref048","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/j.1472-8206.1999.tb00334.x","article-title":"Gastrointestinal absorption of drugs: Methods and studies","volume":"13","author":"L. Barthe","year":"1999","journal-title":"Fundam. Clin. Pharmacol"},{"issue":"4","key":"pone.0284539.ref049","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/08998280.2000.11927719","article-title":"Drug Interactions Due to Cytochrome P450","volume":"13","author":"C. C. Ogu","year":"2000","journal-title":"Baylor Univ. Med. Cent. Proc"},{"issue":"Suppl 10","key":"pone.0284539.ref050","article-title":"Computational determination of hERG-related cardiotoxicity of drug candidates","volume":"20","author":"H. M. Lee","year":"2019","journal-title":"BMC Bioinformatics"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0284539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T17:49:00Z","timestamp":1682012940000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0284539"}},"subtitle":[],"editor":[{"given":"Arabinda","family":"Ghosh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,20]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0284539","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,20]]}}}