In silico discovery of potential drug molecules to improve the treatment of isoniazid-resistant Mycobacterium tuberculosis.
J Biomol Struct Dyn
; 37(13): 3388-3398, 2019 08.
Article
in En
| MEDLINE
| ID: mdl-30132739
ABSTRACT
The emergence of multidrug-resistant Mycobacterium tuberculosis (M.tb) has become one of the major hurdles in the treatment of tuberculosis (TB). Drug-resistant M.tb has evolved with various strategies to avoid killing by the anti-tubercular drugs. Thus, there is a rising need to develop effective anti-TB drugs to improve the treatment of these strains. Traditional drug design approach has earned little success due to time and the cost involved in the process of development of anti-infective drugs. Numerous reports have demonstrated that several mutations in the drug target sites cause emergence of drug-resistant M.tb strains. In this study, we performed computational mutational analysis of M.tb inhA, fabD, and ahpC genes, which are the primary targets for first-line isoniazid (INH) drug. In silico virtual drug screening was performed to identify the potent drugs from a ChEMBL compound library to improve the treatment of INH-resistant M.tb. Further, these compounds were analyzed for their binding efficiency against active drug binding cavity of M.tb wild-type and mutant InhA, FabD and AhpC proteins. The drug efficacy of predicted lead compounds was verified by molecular docking using M.tb wild-type and mutant InhA, FabD and AhpC protein template models. Different in silico and pharmacophore analysis predicted three potent lead compounds with better drug-like properties against both M.tb wild-type and mutant InhA, FabD, and AhpC proteins as compared to INH drug, and thus may be considered as effective drugs for the treatment of INH-resistant M.tb strains. We hypothesize that this work may accelerate drug discovery process for the treatment of drug-resistant TB. Communicated by Ramaswamy H. Sarma.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bacterial Proteins
/
Computer Simulation
/
Mutant Proteins
/
Drug Discovery
/
Isoniazid
/
Mycobacterium tuberculosis
/
Antitubercular Agents
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Biomol Struct Dyn
Year:
2019
Document type:
Article
Affiliation country:
India