期刊
BIOORGANIC CHEMISTRY
卷 80, 期 -, 页码 319-333出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2018.04.022
关键词
Mtb-DHFR inhibitors; Antimycobacterial; Indole moiety; 1DF7; 1OHJ; Antitubercular; Consensus docking
资金
- Department of Biotechnology (DBT), Govt of India [AS/MP (RES.)/JH-5/2013]
- TAACF (Tuberculosis Antimicrobial Acquisition Coordinating Facility, National Institute of Allergy and Infectious Diseases , USA [HHSN272201100009I]
Tuberculosis is an infectious disease that affects millions of population every year. Mtb-DHFR is a validated target that is vital for nucleic acids biosynthesis and therefore DNA formation and cell replication. This paper report identification and synthesis of novel compounds for selective inhibition of Mtb-DHFR and unleash the selective structural features necessary to inhibit the same. Virtual screening of databases was carried out to identify novel compounds on the basis of difference between the binding pockets of the two proteins. Consensus docking was performed to improve upon the results and best ten hits were selected. Hit 1 was subjected to analogues design and the analogues were docked against Mtb-DHFR. From the docking results 11 compounds were selected for synthesis and biological assay against H-37 Rv. Most potent compound (IND-07) was tested for selectivity using enzymatic assay against Mtb-DHFR and h-DHFR. The compounds were found to have good inhibitory activity (25-200 mu M) against H-37 Rv and in enzyme assay against Mtb-DHFR and h-DHFR the compound was found selective towards Mtb-DHFR with selectivity index of 6.53. This work helped to identify indole moiety as novel scaffold for development of novel selective Mtb-DHFR inhibitors as antimycobacterial agents.
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