title: Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches.
abstract: 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.
authors.affiliation: National Hellenic Research Foundation (NHRF), Institute of Biology, Medicinal Chemistry and Biotechnology (IBMCB), Vassileos-Constantinou-Ave. 48, 11635, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Xanthopoulos
authors.affiliation: National Hellenic Research Foundation (NHRF), Institute of Biology, Medicinal Chemistry and Biotechnology (IBMCB), Vassileos-Constantinou-Ave. 48, 11635, Athens, Greece.|School of Chemical Engineering, National Technical University of Athens (NTUA), Organic Synthesis Laboratory, Iroon-Polytechneiou-Str. 9, 15773, Athens, Greece.
authors.forename: Eftichia
authors.initials: E
authors.lastname: Kritsi
authors.affiliation: Neurofarba Dept., Sezione di Scienze farmaceutiche e nutraceutiche, e Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Rm. 188, Via UgoSchiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: National Hellenic Research Foundation (NHRF), Institute of Biology, Medicinal Chemistry and Biotechnology (IBMCB), Vassileos-Constantinou-Ave. 48, 11635, Athens, Greece.
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.affiliation: National Hellenic Research Foundation (NHRF), Institute of Biology, Medicinal Chemistry and Biotechnology (IBMCB), Vassileos-Constantinou-Ave. 48, 11635, Athens, Greece. gleonis@eie.gr.
authors.forename: Georgios
authors.initials: G
authors.lastname: Leonis
authors.affiliation: National Hellenic Research Foundation (NHRF), Institute of Biology, Medicinal Chemistry and Biotechnology (IBMCB), Vassileos-Constantinou-Ave. 48, 11635, Athens, Greece. pzoump@eie.gr.
authors.forename: Panagiotis
authors.identifier: 0000-0001-9348-6078
authors.initials: P
authors.lastname: Zoumpoulakis
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry*; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D055808:Drug Discovery; D015497:HIV-1; D057166:High-Throughput Screening Assays; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation
chemical_list: D019380:Anti-HIV Agents; D057055:Aspartic Acid Proteases
keywords: HIV; drug discovery; inhibitors; molecular modeling; proteases