title: Hierarchical database screenings for HIV-1 reverse transcriptase using a pharmacophore model, rigid docking, solvation docking, and MM-PB/SA.
abstract: In this work, an efficient strategy was presented to search drug leads for human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) using hierarchical database screenings, which included a pharmacophore model, multiple-conformation rigid docking, solvation docking, and molecular mechanics-Poisson-Boltzmann/surface area (MM-PB/SA) sequentially. Encouraging results were achieved in searching a refined available chemical directory (ACD) database: the enrichment factor after the first three filters was estimated to be 25-fold; the hit rate for all the four filters was predicted to be 41% in a control test using 37 known HIV-1 non-nucleoside reverse transcriptase inhibitors; 10 out of 30 promising solvation-docking hits had MM-PB/SA binding free energies better than -6.8 kcal/mol and the best one, HIT15, had -17.0 kcal/mol. In conclusion, the hierarchical multiple-filter database searching strategy is an attractive strategy in drug lead exploration.
authors.affiliation: Encysive Pharmaceuticals Inc., 7000 Fannin, Houston, Texas 77030, USA. jwang@encysive.com
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Xinshan
authors.initials: X
authors.lastname: Kang
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D000495:Allosteric Site; D019380:Anti-HIV Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013223:Statistics as Topic; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase