Hologram quantitative structure–activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors

Abstract

Uiaran de Oliveira Magalhães,1 Alessandra Mendonça Teles de Souza,1 Magaly Girão Albuquerque,2 Monique Araújo de Brito,3 Murilo Lamim Bello,1 Lucio Mendes Cabral,4 Carlos Rangel Rodrigues1 1Universidade Federal do Rio de Janeiro (UFRJ), Faculdade de Farmácia, Laboratório de Modelagem Molecular and QSAR (ModMolQSAR), Rio de Janeiro, RJ, Brazil; 2Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Química, Laboratório de Modelagem Molecular (LabMMol), Rio de Janeiro, RJ, Brazil; 3Universidade Federal Fluminense (UFF), Faculdade de Farmácia, Laboratório de Química Medicinal Computacional (LabQMC), Niterói, RJ, Brazil; 4Universidade Federal do Rio de Janeiro (UFRJ), Faculdade de Farmácia, Laboratório de Tecnologia Farmacêutica Industrial (LabTIF), Rio de Janeiro, RJ, Brazil Abstract: Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure–activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure–activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q2 = 0.802, r2 = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2–5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q2 = 0.748, r2 = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives. Keywords: 3D-QSAR, AIDS, CoMFA, HQSAR, 2D/3D-QSAR