Predicting kinase inhibitors using bioactivity matrix derived informer sets

PLoS Comput Biol. 2019 Aug 5;15(8):e1006813. doi: 10.1371/journal.pcbi.1006813. eCollection 2019 Aug.

Abstract

Prediction of compounds that are active against a desired biological target is a common step in drug discovery efforts. Virtual screening methods seek some active-enriched fraction of a library for experimental testing. Where data are too scarce to train supervised learning models for compound prioritization, initial screening must provide the necessary data. Commonly, such an initial library is selected on the basis of chemical diversity by some pseudo-random process (for example, the first few plates of a larger library) or by selecting an entire smaller library. These approaches may not produce a sufficient number or diversity of actives. An alternative approach is to select an informer set of screening compounds on the basis of chemogenomic information from previous testing of compounds against a large number of targets. We compare different ways of using chemogenomic data to choose a small informer set of compounds based on previously measured bioactivity data. We develop this Informer-Based-Ranking (IBR) approach using the Published Kinase Inhibitor Sets (PKIS) as the chemogenomic data to select the informer sets. We test the informer compounds on a target that is not part of the chemogenomic data, then predict the activity of the remaining compounds based on the experimental informer data and the chemogenomic data. Through new chemical screening experiments, we demonstrate the utility of IBR strategies in a prospective test on three kinase targets not included in the PKIS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cheminformatics / methods
  • Cheminformatics / statistics & numerical data
  • Computational Biology
  • Computer Simulation
  • Databases, Chemical
  • Databases, Pharmaceutical
  • Drug Discovery / methods*
  • Drug Discovery / statistics & numerical data
  • Drug Evaluation, Preclinical / methods
  • Drug Evaluation, Preclinical / statistics & numerical data
  • High-Throughput Screening Assays / methods
  • High-Throughput Screening Assays / statistics & numerical data
  • Humans
  • Prospective Studies
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protozoan Proteins
  • Structure-Activity Relationship
  • User-Computer Interface
  • Viral Proteins / antagonists & inhibitors

Substances

  • Protein Kinase Inhibitors
  • Protozoan Proteins
  • Viral Proteins
  • BGLF4 protein, Epstein-Barr virus
  • PknB protein, Mycobacterium tuberculosis
  • Protein Serine-Threonine Kinases
  • ROP18 protein, Toxoplasma gondii