%0 Journal Article %A Xanthopoulos D.%A %A Kritsi E.%A %A Supuran C.T.%A %A Papadopoulos M.G.%A %A Leonis G.%A %A Zoumpoulakis P. %D 2016 %T Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches %J ChemMedChem %@ 1860-7179 %R 10.1002/cmdc.201600220 %I John Wiley and Sons Ltd %P 1646–1652 %U https://hdl.handle.net/10442/17506 %X 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−1and 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. %> Αποθετήριο Ήλιος / ΕΙΕ