title: Characterization of small molecule binding. I. Accurate identification of strong inhibitors in virtual screening.
abstract: Accurately ranking docking poses remains a great challenge in computer-aided drug design. In this study, we present an integrated approach called MIEC-SVM that combines structure modeling and statistical learning to characterize protein-ligand binding based on the complex structure generated from docking. Using the HIV-1 protease as a model system, we showed that MIEC-SVM can successfully rank the docking poses and consistently outperformed the state-of-art scoring functions when the true positives only account for 1% or 0.5% of all the compounds under consideration. More excitingly, we found that MIEC-SVM can achieve a significant enrichment in virtual screening even when trained on a set of known inhibitors as small as 50, especially when enhanced by a model average approach. Given these features of MIEC-SVM, we believe it provides a powerful tool for searching for and designing new drugs.
authors.affiliation: Department of Chemistry and Biochemistry, UCSD, La Jolla, California 92093-0359, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D004353:Drug Evaluation, Preclinical; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012997:Solvents / Q000737:chemistry; D060388:Support Vector Machine; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D012997:Solvents; D016333:HIV Protease