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Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches
Author(s) -
Xanthopoulos Dimitrios,
Kritsi Eftichia,
Supuran Claudiu T.,
Papadopoulos Manthos G.,
Leonis Georgios,
Zoumpoulakis Panagiotis
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600220
Subject(s) - pharmacophore , molecular mechanics , protease , virtual screening , hiv 1 protease , chemistry , van der waals force , hydrogen bond , molecular dynamics , ligand (biochemistry) , interaction energy , computational chemistry , stereochemistry , combinatorial chemistry , enzyme , biochemistry , molecule , organic chemistry , receptor
A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson–Boltzmann surface area free‐energy calculations for the five ligand–HIV PR complexes suggested a high stability of the systems through hydrogen‐bond interactions between the ligands and the protease's flaps (Ile50/50′), as well as interactions with residues of the active site (Asp25/25′/29/29′/30/30′). Binding‐energy calculations for the three most promising compounds yielded values between −5 and −10 kcal mol −1 and suggested that van der Waals interactions contribute most favorably to the total energy. The predicted binding‐energy values were verified by in vitro inhibition assays, which showed promising results in the high nanomolar range. These results provide structural considerations that may guide further hit‐to‐lead optimization toward improved anti‐HIV drugs.