title: Using Hierarchical Virtual Screening To Combat Drug Resistance of the HIV-1 Protease.
abstract: Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of highly active anti-retroviral therapy (HAART) that block the catalytic site of HIV protease, thus preventing maturation of the HIV virion. However, with two decades of PI prescriptions in clinical practice, drug-resistant HIV mutants have now been found for all of the PI drugs. Therefore, the continuous development of new PI drugs is crucial both to combat the existing drug-resistant HIV strains and to provide treatments for future patients. Here we purpose an HIV PI drug design strategy to select candidate PIs with binding energy distributions dominated by interactions with conserved protease residues in both wild-type and various drug-resistant mutants. On the basis of this strategy, we have constructed a virtual screening pipeline including combinatorial library construction, combinatorial docking, MM/GBSA-based rescoring, and reranking on the basis of the binding energy distribution. We have tested our strategy on lopinavir by modifying its two functional groups. From an initial 751 689 candidate molecules, 18 candidate inhibitors were selected using the pipeline for experimental validation. IC50 measurements and drug resistance predictions successfully identified two ligands with both HIV protease inhibitor activity and an improved drug resistance profile on 2382 HIV mutants. This study provides a proof of concept for the integration of MM/GBSA energy analysis and drug resistance information at the stage of virtual screening and sheds light on future HIV drug design and the use of virtual screening to combat drug resistance.
authors.affiliation: †Department of Chemistry and Biochemistry University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0359, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: †Department of Chemistry and Biochemistry University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0359, United States.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Ainsworth
authors.affiliation: †Department of Chemistry and Biochemistry University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0359, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.affiliation: ‡College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.affiliation: †Department of Chemistry and Biochemistry University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0359, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1