Computational screening for new inhibitors of M. tuberculosis mycolyltransferases antigen 85 group of proteins as potential drug targets
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Computational screening for new inhibitors of M.
tuberculosis mycolyltransferases antigen 85 group of
proteins as potential drug targets
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| Creator |
Gahoi, Shachi
Mandal, Rahul Shubhra Ivanisenko, Nikita Shrivastava, Priyanka Jain, Sriyans Singha, Ashish Kumar Raghunandanan, Muthukurrusi Varieth Kanchan, Swarna Taneja, Bhupesh Mandal, Chhabinath Ivanisenko, Vladimir A Kumar, Rita Kumar, Anil Ramachandran, Srinivasan |
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| Subject |
Molecular & Human Genetics
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| Description |
The group of antigen 85 proteins of Mycobacterium tuberculosis is responsible for converting trehalose monomycolate to
trehalose dimycolate, which contributes to cell wall stability. Here, we have used a serial enrichment approach to identify
new potential inhibitors by searching the libraries of compounds using both 2D atom pair descriptors and binary fingerprints
followed by molecular docking. Three different docking softwares AutoDock, GOLD, and LigandFit were used for
docking calculations. In addition, we applied the criteria of selecting compounds with binding efficiency close to the starting
known inhibitor and showing potential to form hydrogen bonds with the active site amino acid residues. The starting
inhibitor was ethyl-3-phenoxybenzyl-butylphosphonate, which had IC50 value of 2.0 μM in mycolyltransferase inhibition
assay. Our search from more than 34 million compounds from public libraries yielded 49 compounds. Subsequently, selection
was restricted to compounds conforming to the Lipinski rule of five and exhibiting hydrogen bonding to any of the
amino acid residues in the active site pocket of all three proteins of antigen 85A, 85B, and 85C. Finally, we selected those
ligands which were ranked top in the table with other known decoys in all the docking results. The compound NIH415032
from tuberculosis antimicrobial acquisition and coordinating facility was further examined using molecular dynamics simulations
for 10 ns. These results showed that the binding is stable, although some of the hydrogen bond atom pairs varied
through the course of simulation. The NIH415032 has antitubercular properties with IC90 at 20 μg/ml (53.023 μM). These
results will be helpful to the medicinal chemists for developing new antitubercular molecules for testing
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| Date |
2013
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/1968/1/JOURNAL_OF_BIOMOLECULAR_STRUCTURE_%26_DYNAMICS__Volume_31_(_1)__Special_Issue_SI___Pages_30%2D43_;2013[149].pdf
Gahoi, Shachi and Mandal, Rahul Shubhra and Ivanisenko, Nikita and Shrivastava, Priyanka and Jain, Sriyans and Singha, Ashish Kumar and Raghunandanan, Muthukurrusi Varieth and Kanchan, Swarna and Taneja, Bhupesh and Mandal, Chhabinath and Ivanisenko, Vladimir A and Kumar, Rita and Kumar, Anil and Ramachandran, Srinivasan (2013) Computational screening for new inhibitors of M. tuberculosis mycolyltransferases antigen 85 group of proteins as potential drug targets. Journal of Biomolecular Structure and Dynamics, 31 (1). pp. 30-43. |
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| Relation |
http://dx.doi.org/10.1080/07391102.2012.691343
http://www.eprints.iicb.res.in/1968/ |
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