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A Quantum Mechanics/Molecular Mechanics Study of the Protein–Ligand Interaction for Inhibitors of HIV‐1 Integrase
Author(s) -
Alves Cláudio N.,
Martí Sergio,
Castillo Raquel,
Andrés Juan,
Moliner Vicent,
Tuñón Iñaki,
Silla Estanislao
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700040
Subject(s) - molecular mechanics , integrase , molecular dynamics , chemistry , ligand (biochemistry) , integrase inhibitor , computational chemistry , human immunodeficiency virus (hiv) , stereochemistry , biochemistry , antiretroviral therapy , biology , dna , virology , receptor , viral load
Human immunodeficiency virus type‐1 integrase (HIV‐1 IN) is an essential enzyme for effective viral replication. Diketo acids such as L‐731,988 and S‐1360 are potent and selective inhibitors of HIV‐1 IN. In this study, we used molecular dynamics simulations, within the hybrid quantum mechanics/molecular mechanics (QM/MM) approach, to determine the protein–ligand interaction energy between HIV‐1 IN and L‐731,988 and 10 of its derivatives and analogues. This hybrid methodology has the advantage that it includes quantum effects such as ligand polarisation upon binding, which can be very important when highly polarisable groups are embedded in anisotropic environments, as for example in metal‐containing active sites. Furthermore, an energy decomposition analysis was performed to determine the contributions of individual residues to the enzyme–inhibitor interactions on averaged structures obtained from rather extensive conformational sampling. Analysis of the results reveals first that there is a correlation between protein–ligand interaction energy and experimental strand transfer into human chromosomes and secondly that the Asn‐155, Lys‐156 and Lys‐159 residues and the Mg 2+ ion are crucial to anti‐HIV IN activity. These results may explain the available experimental data.