Pharmaceutical Research

, Volume 31, Issue 2, pp 414–435 | Cite as

Combining Computational Methods for Hit to Lead Optimization in Mycobacterium Tuberculosis Drug Discovery

  • Sean Ekins
  • Joel S. Freundlich
  • Judith V. Hobrath
  • E. Lucile White
  • Robert C. Reynolds
Research Paper



Tuberculosis treatments need to be shorter and overcome drug resistance. Our previous large scale phenotypic high-throughput screening against Mycobacterium tuberculosis (Mtb) has identified 737 active compounds and thousands that are inactive. We have used this data for building computational models as an approach to minimize the number of compounds tested.


A cheminformatics clustering approach followed by Bayesian machine learning models (based on publicly available Mtb screening data) was used to illustrate that application of these models for screening set selections can enrich the hit rate.


In order to explore chemical diversity around active cluster scaffolds of the dose–response hits obtained from our previous Mtb screens a set of 1924 commercially available molecules have been selected and evaluated for antitubercular activity and cytotoxicity using Vero, THP-1 and HepG2 cell lines with 4.3%, 4.2% and 2.7% hit rates, respectively. We demonstrate that models incorporating antitubercular and cytotoxicity data in Vero cells can significantly enrich the selection of non-toxic actives compared to random selection. Across all cell lines, the Molecular Libraries Small Molecule Repository (MLSMR) and cytotoxicity model identified ~10% of the hits in the top 1% screened (>10 fold enrichment). We also showed that seven out of nine Mtb active compounds from different academic published studies and eight out of eleven Mtb active compounds from a pharmaceutical screen (GSK) would have been identified by these Bayesian models.


Combining clustering and Bayesian models represents a useful strategy for compound prioritization and hit-to lead optimization of antitubercular agents.


bayesian models clustering Collaborative Drug Discovery Tuberculosis database dual-event models function class fingerprints lead optimization Mycobacterium tuberculosis tuberculosis 



S.E. acknowledges colleagues at CDD. Accelrys are kindly acknowledged for providing Discovery Studio. The Bayesian models created in Discovery Studio are available from the authors upon written request.

The CDD TB has been developed thanks to funding from the Bill and Melinda Gates Foundation (Grant#49852 “Collaborative drug discovery for TB through a novel database of SAR data optimized to promote data archiving and sharing”).

R.C.R. acknowledges the American Reinvestment and Recovery Act Grant 1RC1AI086677-01 that provided support for the presented study (National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID)) – “Targeting MDR-Tuberculosis.”

S.E. acknowledges that the Bayesian models described were developed with support from Award Number R43 LM011152-01 “Biocomputation across distributed private datasets to enhance drug discovery” from the National Library of Medicine.

J.S.F. acknowledges funding from UMDNJ–NJMS and the Foundation of UMDNJ.

SE is a consultant for Collaborative Drug Discovery, Inc.

Supplementary material

11095_2013_1172_MOESM1_ESM.xlsx (1.6 mb)
Table S1 1924 molecules with data used in this study with Bayesian model predictions. The complete dataset created under this grant is available as a public dataset TB: ARRA which is available upon registration (XLSX 1619 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sean Ekins
    • 1
    • 2
  • Joel S. Freundlich
    • 3
    • 4
  • Judith V. Hobrath
    • 5
  • E. Lucile White
    • 5
  • Robert C. Reynolds
    • 5
    • 6
  1. 1.Collaborative Drug DiscoveryBurlingameUSA
  2. 2.Collaborations in ChemistryFuquay-VarinaUSA
  3. 3.Department of MedicineCenter for Emerging and Reemerging Pathogens Rutgers University–New Jersey Medical SchoolNewarkUSA
  4. 4.Department of Pharmacology & PhysiologyRutgers University–New Jersey Medical SchoolNewarkUSA
  5. 5.Drug Discovery DivisionSouthern Research InstituteBirminghamUSA
  6. 6.Department of ChemistryUniversity of Alabama at Birmingham College of Arts and SciencesBirminghamUSA

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