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However, resistance owing to mutations challenge the long\u2010term efficacy in the medication of HIV\u20101\u2010infected individuals. Lopinavir (LPV) and darunavir (DRV), two second\u2010generation drugs are the most potent among PIs, hustling the drug resistance when mutations occur in the active and nonactive site of the protease (PR). Herein, we strive for compounds that can stifle the function of wild\u2010type (WT) HIV\u20101 PR along with four major single mutants (I54M, V82T, I84V, and L90M) instigating resistance to the PIs using <jats:italic>in silico<\/jats:italic> approach. Six common compounds are retrieved from six databases using combined pharmacophore\u2010based and structure\u2010based virtual screening methodology. LPV and DRV are docked and the binding free energy is calculated to set the cut\u2010off value for selecting compounds. Further, to gain insight into the stability of the complexes the molecular dynamics simulation (MDS) is carried out, which uncovers two lead molecules namely NCI\u2010524545 and ZINC12866729. Both the lead molecules connect with WT and mutant HIV\u20101 PRs through strong and stable hydrogen bond interactions when compared with LPV and DRV throughout the trajectory analysis. Interestingly, NCI\u2010524545 and ZINC12866729 exhibit direct interactions with I50\/50\u2032 by replacing the conserved water molecule as evidenced by MDS, which indicates the credible potency of these compounds. Hence, we\u00a0concluded that NCI\u2010524545 and ZINC12866729 have great puissant to restrain the role of drug resistance HIV\u20101 PR variants, which can also show better activity through in vivo and in vitro conditions.<\/jats:p>","DOI":"10.1002\/jcb.28181","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T08:16:32Z","timestamp":1543824992000},"page":"9063-9081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["An <i>in silico<\/i> pharmacological approach toward the discovery of potent inhibitors to combat drug resistance HIV\u20101 protease variants"],"prefix":"10.1002","volume":"120","author":[{"given":"Chirasmita","family":"Nayak","sequence":"first","affiliation":[{"name":"Computer Aided Drug Design and Molecular Modeling, Department of Bioinformatics Alagappa University Karaikudi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ishwar","family":"Chandra","sequence":"additional","affiliation":[{"name":"Computer Aided Drug Design and Molecular Modeling, Department of Bioinformatics Alagappa University Karaikudi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4153-6437","authenticated-orcid":false,"given":"Sanjeev Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Computer Aided Drug Design and Molecular Modeling, Department of Bioinformatics Alagappa University Karaikudi India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,12,3]]},"reference":[{"key":"e_1_2_7_1_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178293"},{"key":"e_1_2_7_1_3_1","unstructured":"UNAIDS Global AIDS Update 2017.2018; Retrieved fromhttp:\/\/www.unaids.org\/en\/resources\/documents\/2017\/2017_data_book. 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