Computational Studies of Dipyridodiazepinones as Human Immunodeficiency Virus ( HIV) Reverse Transcriptase Inhibitors
Reiner G. Villavicencio and Junie B. Billones*
Department of Physical Sciences and Mathematics, College of Arts and Sciences,
University of the Philippines Manila, Padre Faura St., Ermita, Manila 1000 Philippines
Hydrophobic interactions of nevirapine with aromatic and aliphatic amino acid residues of the wild type reverse transcriptase.
A series of dipyridodiazepinone derivatives that are highly active against wild-type and K103N – Y181C double mutant reverse transcriptase were computationally investigated. Quantitative structure-activity relationship (QSAR) studies, metabolic studies, and docking simulations were performed on these compounds. The logP value and the HOMO-LUMO energies of the compound were found to be critical for activity. The most probable biotransformation reactions include N5 / N11-dealkylation, aliphatic hydroxylation/oxidation at the ethoxy connector, and aromatic hydroxylation in the dipyridodiazepinone nucleus and the aryl group. Docking studies showed that the inhibitor must have at least two aromatic structures to maintain interactions with the Tyr181 – Tyr188 pocket and the Tyr318 region. The nucleus of the molecule must be a hydrophobic structure to interact with Val179 and Gly190 and must be substituted with H-bonding functional groups to interact with Lys101 and Lys/Asn 103.
Acquired Immunodeficiency Syndrome (AIDS) is the disease caused by the human immunodeficiency virus (HIV). HIV contains its genome on RNA strands and for it to insert the genetic material in the genome of the host, a DNA copy of the single-stranded RNA should first be synthesized. This reversal of the transcription process is performed by the enzyme reverse transcriptase. Reverse transcriptase is a multifunctional enzyme with an RNA-directed DNA polymerase, DNA-directed DNA polymerase, and an RNAse H activity. The three dimensional conformation of the enzyme consist of a large claw-shaped active site. It is a heterodimer with a 66-kDa (p66) and a 51-kDa (p51) subunit, which are coded by the same gene (Kohlstaedt et al. 1992; Jacobo-Molina et al. 1993; Smerdon et al. 1994; Tantillo et al. 1994; Ding et al. 1995; Ren et al. 1995).
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