title: Inhibitor ranking through QM based chelation calculations for virtual screening of HIV-1 RNase H inhibition.
abstract: Quantum mechanical (QM) calculations have been used to predict the binding affinity of a set of ligands towards HIV-1 RT associated RNase H (RNH). The QM based chelation calculations show improved binding affinity prediction for the inhibitors compared to using an empirical scoring function. Furthermore, full protein fragment molecular orbital (FMO) calculations were conducted and subsequently analysed for individual residue stabilization/destabilization energy contributions to the overall binding affinity in order to better understand the true and false predictions. After a successful assessment of the methods based on the use of a training set of molecules, QM based chelation calculations were used as filter in virtual screening of compounds in the ZINC database. By this, we find, compared to regular docking, QM based chelation calculations to significantly reduce the large number of false positives. Thus, the computational models tested in this study could be useful as high throughput filters for searching HIV-1 RNase H active-site molecules in the virtual screening process.
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Vasanthanathan
authors.initials: V
authors.lastname: Poongavanam
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Casper
authors.initials: C
authors.lastname: Steinmann
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Kongsted
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D055808:Drug Discovery; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D016914:Ribonuclease H