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Title: Structure based drug design and in vitro biological screening for various enzymes of mycobacterium tuberculosis
Researcher: Saxena, Shalini
Guide(s): Sriram, D.
Keywords: Based Drug Design,Biological Screening,Mycobacterium tuberculosis
University: Birla Institute of Technology and Science
Completed Date: 1/8/2015
Abstract: In the present study we explore the pharmaceutically underexploited domains of M. tuberculosis DNA Gyrase B (GyrB) and L-Alanine dehydrogenase (L-AlaDH) as potential platform for developing novel agents that target M. tuberculosis which is an air born infection that has infected one third of the world population. newlineUtilizing the computational tools of structure based and ligand based drug design methods; 5-phenyl-2-C-thiophene-2-thiophene-2,3-diamido was identified as potential DNA Gyrase B lead and 5-(4-benzyloxy)benzylidene-2-imino-3-(5-nitrothiazol-2-yl)thiazolidin-4-one and 2-(5-nitrothiophene-2-carboxamido)-4,5-dihydro-N6-(4-methoxyphenyl)thieno[2,3-c]pyridine-3,6(7H) dicarboxamide were identified as M. tuberculosis L-AlaDH leads. newlineThe leads obtained from both the targets were further customized using a combination of molecular docking and chemical synthesis to develop various analogues that displayed considerable in vitro enzyme efficacy and bactericidality activity against M. tuberculosis H37Rv strain. newlineBy using structure based approach, compound S23 emerged as the most potent GyrB lead with M. smegmatis GyrB IC50 of 1.35±0.58 and#956;M; supercoiling inhibitory IC50 value of 0.86±0.25 and#956;M; M. tuberculosis MIC of 4.84 and#956;M. The binding affinity of the potent ligand towards the GyrB domain was re-ascertained by differential scanning fluorimetry experiment wherein a shift in the melting temperature TM was monitored. The tested compounds brought a positive shift in TM in the range of 2-3.1°C compared to the native protein, a repercussion of strong inhibitor binding. newlineSimilarly, for the identification of M. tuberculosis L-AlaDH inhibitors, an e-pharmcophore based high throughput virtual screening protocol was used. Since no inhibitors were reported till date for M. tuberculosis L-AlaDH, thus we have report the first set of novel diverse inhibitors using crystal structure of M. tuberculosis L-AlaDH protein complex with N6-methyl adenosine and substrate NAD+. Two molecules identified as leads were modified synthetically to obta
Pagination: xvii
Appears in Departments:Pharmacy

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