Calculation of binding energy using BLYP/MM for the HIV-1 integrase complexed with the S-1360 and two analogues.

Sergio Martí, Iñaki Tuñón, Vicent Moliner, Juan Andrés, Cláudio N Alves, Raquel Castillo, Estanislao Silla

Journal: Bioorganic & medicinal chemistry 2007;15(11):3818-24

PMID: 17420131

Full Text on Elsevier Science View on PubMed

Abstract

Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. S-1360 is a potent and selective inhibitor of HIV-1 IN. In this work, we have carried out molecular dynamics (MD) simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) approach, to determine the protein-ligand interaction energy for S-1360 and two analogues. Analysis of the MD trajectories reveals that the strongest protein-inhibitor interactions, observed in the three studied complexes, are established with Lys-159 residue and Mg(2+) cation. Calculations of binding energy using BLYP/MM level of theory reveal that there is a direct relationship between this theoretical computed property and the experimental determined anti-HIV activity.

Address: Departamento de Química, Centro de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110 Belém, PA, Brazil. [email protected]

DOI: 10.1016/j.bmc.2007.03.027

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MeSH Terms: Amino Acid Sequence, Amino Acid Substitution, Crystallography, X-Ray, Furans, HIV Integrase, HIV Integrase Inhibitors, Humans, Lysine, Magnesium, Models, Chemical, Propane, Protein Conformation, Pyrroles, Structure-Activity Relationship, Triazoles