Finding Druggable Sites in Proteins Using TACTICS

Daniel J. Evans, Remy A. Yovanno, Sanim Rahman, David W. Cao, Morgan Q. Beckett, Milan H. Patel, Afif F. Bandak, Albert Y. Lau

Research output: Contribution to journalArticlepeer-review


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

Original languageEnglish (US)
Pages (from-to)2897-2910
Number of pages14
JournalJournal of Chemical Information and Modeling
Issue number6
StatePublished - Jun 28 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences


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