Open AccessFinding Druggable Sites in Proteins Using TACTICS
Author(s) -
Daniel J. Evans,
Remy A. Yovanno,
Sanim Rahman,
David W. Cao,
Morgan Q. Beckett,
Mayank Patel,
Afif F. Bandak,
Albert Y. Lau
Publication year - 2021
Publication title -
journal of chemical information and modeling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 160
eISSN - 1549-960X
pISSN - 1549-9596
DOI - 10.1021/acs.jcim.1c00204
Subject(s) - druggability , computational biology , drug discovery , computer science , binding site , molecular dynamics , bacteriorhodopsin , docking (animal) , cluster analysis , protein structure , chemistry , biology , artificial intelligence , biochemistry , computational chemistry , medicine , gene , nursing , membrane
Structure-based drug discovery efforts require knowledge of where drug-binding sites are located on target proteins. To address the challenge of finding druggable sites, we developed a machine-learning algorithm called TACTICS (trajectory-based analysis of conformations to identify cryptic sites), which uses an ensemble of molecular structures (such as molecular dynamics simulation data) as input. First, TACTICS uses k -means clustering to select a small number of conformations that represent the overall conformational heterogeneity of the data. Then, TACTICS uses a random forest model to identify potentially bindable residues in each selected conformation, based on protein motion and geometry. Lastly, residues in possible binding pockets are scored using fragment docking. As proof-of-principle, TACTICS was applied to the analysis of simulations of the SARS-CoV-2 main protease and methyltransferase and the Yersinia pestis aryl carrier protein. Our approach recapitulates known small-molecule binding sites and predicts the locations of sites not previously observed in experimentally determined structures. The TACTICS code is available at https://github.com/Albert-Lau-Lab/tactics_protein_analysis.