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

• Published in: Bioorganic & medicinal chemistry 2007-06, Vol.15 (11), p.3818-3824
• Main Authors: Alves, Cláudio N., Martí, Sergio, Castillo, Raquel, Andrés, Juan, Moliner, Vicent, Tuñón, Iñaki, Silla, Estanislao
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding energy; Biological and medical sciences; BLYP/MM; Crystallography, X-Ray; DFT; Furans - chemistry; HIV Integrase - chemistry; HIV Integrase Inhibitors - chemistry; HIV-1; Humans; Lysine - chemistry; Magnesium - chemistry; Medical sciences; Models, Chemical; Molecular dynamics (MD); Pharmacology. Drug treatments; Propane - analogs & derivatives; Propane - chemistry; Protein Conformation; Pyrroles - chemistry; Quantum mechanical/molecular mechanical (QM/MM); S-1360; Structure-Activity Relationship; Triazoles - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.03.027

Representation of the most important interactions between the S-1360 and HIV-1 integrase. 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.