Molecular Docking-Based Screening for Novel Inhibitors of the Human Immunodeficiency Virus Type 1 Protease that Effectively Reduce the Viral Replication in Human Cells.

Autor:	Mavian C; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA., Coman RM; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.; Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA., Zhang X; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA., Pomeroy S; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA., Ostrov DA; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA., Dunn BM; Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA., Sleasman JW; Pediatric Allergy, Immunology, and Pulmonary Medicine, Duke University, Durham, NC 27710, USA., Goodenow MM; Office of AIDS Research, National Institutes of Health, USA.
Jazyk:	angličtina
Zdroj:	Journal of AIDS & clinical research [J AIDS Clin Res] 2021; Vol. 12 (5). Date of Electronic Publication: 2021 May 21.
Abstrakt:	Therapeutic pressure by protease inhibitors (PIs) contributes to accumulation of mutations in the HIV type 1 (HIV-1) protease (PR) leading to development of drug resistance with subsequent therapy failure. Current PIs target the active site of PR in a competitive manner. Identification of molecules that exploit non-active site mechanisms of inhibition is essential to overcome resistance to current PIs. Potential non-active site HIV-1 protease (PR) inhibitors (PI) were identified by in silico screening of almost 140,000 molecules targeting the hinge region of PR. Inhibitory activity of best docking compounds was tested in an in vitro PR inhibition biochemical assay. Five compounds inhibited PR from multiple HIV-1 sub-types in vitro and reduced replicative capacity by PI-sensitive or multi-PI resistant HIV-1 variants in human cells ex vivo . Antiviral activity was boosted when combined with Ritonavir, potentially diminishing development of drug resistance, while providing effective treatment for drug resistant HIV-1 variants. Competing Interests: Conflict of Interest The authors have no conflict of interest.
Databáze:	MEDLINE
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