title: P1 and P1' para-fluoro phenyl groups show enhanced binding and favorable predicted pharmacological properties: structure-based virtual screening of extended lopinavir analogs against multi-drug resistant HIV-1 protease.
abstract: Crystal structure of multidrug-resistant (MDR) clinical isolate 769, human immunodeficiency virus type-1 (HIV-1) protease in complex with lopinavir (LPV) (PDB ID: 1RV7) showed altered binding orientation of LPV in the expanded active site cavity, causing loss of contacts and decrease in potency. In the current study, with a goal to restore the lost contacts, three libraries of LPV analogs containing extended P1 and/or P1' phenyl groups were designed and docked into the expanded active site cavity of the MDR769 HIV-1 protease. The compounds were then ranked based on three criteria: binding affinity, overall binding profile and predicted pharmacological properties. Among the twelve proposed extensions in different combinations, compound 14 (consists of para-fluoro phenyl group as both P1 and P1' moieties) was identified as a lead with improved binding profile, binding affinity against the MDR protease and favorable predicted pharmacological properties comparable to those of LPV. The binding affinity of 14 against wild type (NL4-3) HIV-1 protease was comparable to that of LPV and was better than LPV against an ensemble of MDR HIV-1 protease variants. Thus, 14 shows enhanced binding affinity by restoring lost contacts in the expanded active site cavity of MDR769 HIV-1 protease variants suggesting that it may have higher potency compared to that of LPV and hence should be further synthesized and evaluated against NL4-3 as well as MDR variants of HIV-1.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA.
authors.forename: Ravikiran S
authors.initials: RS
authors.lastname: Yedidi
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA.
authors.forename: Iulia A
authors.initials: IA
authors.lastname: Kovari
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St., QF305B, Charleston, SC 29425, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA. Electronic address: kovari@med.wayne.edu.
authors.forename: Ladislau C
authors.initials: LC
authors.lastname: Kovari
mesh_terms: D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D061466:Lopinavir / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D061466:Lopinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: HIV-1 protease; HIV/AIDS; Lopinavir; Multidrug-resistance; Protease inhibitors; Virtual screening