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Journal of medicinal chemistry
09 10, 2020;63 (17): 8917-8955.

Molecule Property Analyses of Active Compounds for .

Vadim Makarov, Elena Salina, Robert C Reynolds, Phyo Phyo Kyaw Zin, Sean Ekins
Author Information
  1. Vadim Makarov: FRC Fundamentals of Biotechnology, Russian Academy of Science, Moscow 119071, Russia.
  2. Elena Salina: FRC Fundamentals of Biotechnology, Russian Academy of Science, Moscow 119071, Russia.
  3. Robert C Reynolds: Department of Medicine, Division of Hematology and Oncology, University of Alabama at Birmingham, NP 2540 J, 1720 Second Avenue South, Birmingham, Alabama 35294-3300, United States.
  4. Phyo Phyo Kyaw Zin: Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States.
  5. Sean Ekins: Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510 Raleigh, North Carolina 27606, United States. ORCID
PMID: 32259446 DOI: 10.1021/acs.jmedchem.9b02075

Abstract

Tuberculosis (TB) continues to claim the lives of around 1.7 million people per year. Most concerning are the reports of multidrug drug resistance. Paradoxically, this global health pandemic is demanding new therapies when resources and interest are waning. However, continued tuberculosis drug discovery is critical to address the global health need and burgeoning multidrug resistance. Many diverse classes of antitubercular compounds have been identified with activity in vitro and in vivo. Our analyses of over 100 active leads are representative of thousands of active compounds generated over the past decade, suggests that they come from few chemical classes or natural product sources. We are therefore repeatedly identifying compounds that are similar to those that preceded them. Our molecule-centered cheminformatics analyses point to the need to dramatically increase the diversity of chemical libraries tested and get outside of the historic property space if we are to generate novel improved antitubercular leads.

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Grants

  1. R01 NS102164/NINDS NIH HHS
  2. R41 AI134561/NIAID NIH HHS

MeSH Term

Antitubercular Agents
Bacterial Proteins
Drug Discovery
Drug Resistance, Bacterial
Humans
Mycobacterium tuberculosis
Nitroimidazoles
Nucleoside-Phosphate Kinase
Structure-Activity Relationship
Tuberculosis

Chemicals

Antitubercular Agents
Bacterial Proteins
Nitroimidazoles
Nucleoside-Phosphate Kinase
dTMP kinase
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review
Article has an altmetric score of 5

Word Cloud

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