Identification of Novel Antimicrobial Compounds Targeting IMycobacterium tuberculosis S/I-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening

The emergence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (M. tuberculosis) has become a major medical problem. S-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identification of novel anti-TB drugs. Dual hierarchical in sil...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2024-03, Vol.29 (6)
Main Authors: Ito, Hazuki, Monobe, Kohei, Okubo, Saya, Aoki, Shunsuke
Format: Article
Language:English
Subjects:
Cells
Developing countries
Drugs
Enzymes
Homocysteine
Hydrolases
Medical research
Medicine, Experimental
Molecular dynamics
Simulation methods
Tuberculosis
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Summary:The emergence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (M. tuberculosis) has become a major medical problem. S-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identification of novel anti-TB drugs. Dual hierarchical in silico Structure-Based Drug Screening was performed using a 3D compound structure library (with over 150 thousand synthetic chemicals) to identify compounds that bind to MtSAHH’s active site. In vitro experiments were conducted to verify whether the nine compounds selected as new drug candidates exhibited growth-inhibitory effects against mycobacteria. Eight of the nine compounds that were predicted by dual hierarchical screening showed growth-inhibitory effects against Mycobacterium smegmatis (M. smegmatis), a model organism for M. tuberculosis. Compound 7 showed the strongest antibacterial activity, with an IC[sub.50] value of 30.2 µM. Compound 7 did not inhibit the growth of Gram-negative bacteria or exert toxic effects on human cells. Molecular dynamics simulations of 40 ns using the MtSAHH–Compound 7 complex structure suggested that Compound 7 interacts stably with the MtSAHH active site. These in silico and in vitro results suggested that Compound 7 is a promising lead compound for the development of new anti-TB drugs.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules29061303