Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

Rupesh U Shelke; Mariam S Degani; Archana Raju; Mukti Kanta Ray; Mysore G R Rajan

doi:10.1002/ardp.201600066

Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

Arch Pharm (Weinheim). 2016 Aug;349(8):602-13. doi: 10.1002/ardp.201600066. Epub 2016 Jun 19.

Authors

Rupesh U Shelke¹, Mariam S Degani¹, Archana Raju¹, Mukti Kanta Ray², Mysore G R Rajan²

Affiliations

¹ Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai, India.
² Radiation Medicine Centre, Tata Memorial Hospital, Parel, Mumbai, India.

PMID: 27320965
DOI: 10.1002/ardp.201600066

Abstract

Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.

Keywords: DHFR; FBDD; Mycobacterium tuberculosis; Nitrogen heterocycles.

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry*
Antitubercular Agents / pharmacology
Drug Design*
Folic Acid Antagonists / chemical synthesis
Folic Acid Antagonists / chemistry*
Folic Acid Antagonists / pharmacology
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology
Inhibitory Concentration 50
Microbial Sensitivity Tests
Molecular Docking Simulation
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Nitrogen / chemistry
Tetrahydrofolate Dehydrogenase / metabolism

Substances

Antitubercular Agents
Folic Acid Antagonists
Heterocyclic Compounds
Tetrahydrofolate Dehydrogenase
Nitrogen