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J Mol Graph Model. 2014 Feb;47:18-24. doi: 10.1016/j.jmgm.2013.10.010. Epub 2013 Nov 1.

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.

Author information

1
Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, 540 E. Canfield Avenue, Detroit, MI 48201, USA.
2
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St., QF305B, Charleston, SC 29425, USA.
3
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.

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.

KEYWORDS:

HIV-1 protease; HIV/AIDS; Lopinavir; Multidrug-resistance; Protease inhibitors; Virtual screening

PMID:
24291501
PMCID:
PMC4520429
DOI:
10.1016/j.jmgm.2013.10.010
[Indexed for MEDLINE]
Free PMC Article

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