Kuwanon‐L as a New Allosteric HIV‐1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation
Copyright policy )Kuwanon‐L as a New Allosteric HIV‐1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation
AbstractHIV‐1 integrase (IN) active site inhibitors are the latest class of drugs approved for HIV treatment. The selection of IN strand‐transfer drug‐resistant HIV strains in patients supports the development of new agents that are active as allosteric IN inhibitors. Here, a docking‐based virtual screening has been applied to a small library of natural ligands to identify new allosteric IN inhibitors that target the sucrose binding pocket. From theoretical studies, kuwanon‐L emerged as the most promising binder and was thus selected for biological studies. Biochemical studies showed that kuwanon‐L is able to inhibit the HIV‐1 IN catalytic activity in the absence and in the presence of LEDGF/p75 protein, the IN dimerization, and the IN/LEDGF binding. Kuwanon‐L also inhibited HIV‐1 replication in cell cultures. Overall, docking and biochemical results suggest that kuwanon‐L binds to an allosteric binding pocket and can be considered an attractive lead for the development of new allosteric IN antiviral agents.
- Roma Tre University Italy
- Vita-Salute San Raffaele University Italy
- Università dell Insubria (Varese) Italy
- KU Leuven Belgium
- Sapienza University of Rome Italy
Allosterism, HIV-1 integrase, Inhibitors, Integrase multimerization, Kuwanon-L, Protein-protein interactions, Biochemistry, Organic chemistry, Molecular medicine, Molecular biology, DYNAMICS, Protein Structure, protein-protein interactions, allosterism; HIV-1 integrase; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions; Allosteric Regulation; Binding Sites; Cell Line; Flavonoids; Flavonolignans; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Docking Simulation; Morus; Plant Roots; Protein Structure, Tertiary; Recombinant Proteins; Virus Replication; Biochemistry; Organic Chemistry; Molecular Medicine; Molecular Biology, HIV Integrase, Virus Replication, 301207 Pharmazeutische Chemie, Plant Roots, Cell Line, SDG 3 - Good Health and Well-being, Allosteric Regulation, HIV-1 integrase, HIV-1/physiology, inhibitors, Humans, HIV Integrase Inhibitors, Recombinant Proteins/biosynthesis, allosterism, Flavonoids, Flavonoids/chemistry, Plant Roots/chemistry, Virus Replication/drug effects, Binding Sites, Morus/chemistry, HIV Integrase/chemistry, SITE, kuwanon-L, DNA, Recombinant Proteins, Protein Structure, Tertiary, inhibitor, Flavonolignans, Molecular Docking Simulation, integrase multimerization, SDG 3 – Gesundheit und Wohlergehen, HIV Integrase Inhibitors/chemistry, HIV-1, allosterism; HIV-1 integrase; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions; biochemistry; organic chemistry; molecular medicine; molecular biology, HIV-1 integrase; allosterism; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions, Morus, Flavonolignans/chemistry, Tertiary, RESISTANCE, 301207 Pharmaceutical chemistry
Allosterism, HIV-1 integrase, Inhibitors, Integrase multimerization, Kuwanon-L, Protein-protein interactions, Biochemistry, Organic chemistry, Molecular medicine, Molecular biology, DYNAMICS, Protein Structure, protein-protein interactions, allosterism; HIV-1 integrase; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions; Allosteric Regulation; Binding Sites; Cell Line; Flavonoids; Flavonolignans; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Docking Simulation; Morus; Plant Roots; Protein Structure, Tertiary; Recombinant Proteins; Virus Replication; Biochemistry; Organic Chemistry; Molecular Medicine; Molecular Biology, HIV Integrase, Virus Replication, 301207 Pharmazeutische Chemie, Plant Roots, Cell Line, SDG 3 - Good Health and Well-being, Allosteric Regulation, HIV-1 integrase, HIV-1/physiology, inhibitors, Humans, HIV Integrase Inhibitors, Recombinant Proteins/biosynthesis, allosterism, Flavonoids, Flavonoids/chemistry, Plant Roots/chemistry, Virus Replication/drug effects, Binding Sites, Morus/chemistry, HIV Integrase/chemistry, SITE, kuwanon-L, DNA, Recombinant Proteins, Protein Structure, Tertiary, inhibitor, Flavonolignans, Molecular Docking Simulation, integrase multimerization, SDG 3 – Gesundheit und Wohlergehen, HIV Integrase Inhibitors/chemistry, HIV-1, allosterism; HIV-1 integrase; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions; biochemistry; organic chemistry; molecular medicine; molecular biology, HIV-1 integrase; allosterism; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions, Morus, Flavonolignans/chemistry, Tertiary, RESISTANCE, 301207 Pharmaceutical chemistry
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