title: Combined approach using ligand efficiency, cross-docking, and antitarget hits for wild-type and drug-resistant Y181C HIV-1 reverse transcriptase.
abstract: New hits against HIV-1 wild-type and Y181C drug-resistant reverse transcriptases were predicted taking into account the possibility of some of the known metabolism interactions. In silico hits against a set of antitargets (i.e., proteins or nucleic acids that are off-targets from the desired pharmaceutical target objective) are used to predict a simple, visual measure of possible interactions for the ligands, which helps to introduce early safety considerations into the design of compounds before lead optimization. This combined approach consists of consensus docking and scoring: cross-docking to a group of wild-type and drug-resistant mutant proteins, ligand efficiency (also called binding efficiency) indices as new ranking measures, pre- and postdocking filters, a set of antitargets and estimation, and minimization of atomic clashes. Diverse, small-molecule compounds with new chemistry (such as a triazine core with aromatic side chains) as well as known drugs for different applications (oxazepam, chlorthalidone) were highly ranked to the targets having binding interactions and functional group spatial arrangements similar to those of known inhibitors, while being moderate to low binders to the antitargets. The results are discussed on the basis of their relevance to medicinal and computational chemistry. Optimization of ligands to targets and off-targets or antitargets is foreseen to be critical for compounds directed at several simultaneous sites.
authors.affiliation: Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia. alfonsog@ut.ee
authors.forename: Alfonso T
authors.initials: AT
authors.lastname: García-Sosa
authors.forename: Sulev
authors.initials: S
authors.lastname: Sild
authors.forename: Kalev
authors.initials: K
authors.lastname: Takkis
authors.forename: Uko
authors.initials: U
authors.lastname: Maran
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019540:Area Under Curve; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D012372:ROC Curve; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D014867:Water; D003577:Cytochrome P-450 Enzyme System; D054303:HIV Reverse Transcriptase