INTERACTIONS OF ISONIAZID AND ITS DERIVATIVES WITH MYCOBACTERIUM TUBERCULOSIS SUSCEPTIBLE ENZYME: MOLECULAR MODELING AND DOCKING STUDIES
| dc.contributor.author | QAMAR, KHAWAJA SOHAIL | |
| dc.date.accessioned | 2016-01-14T06:28:46Z | |
| dc.date.available | 2016-01-14T06:28:46Z | |
| dc.date.issued | 2004-08 | |
| dc.description.abstract | In this study, the molecular basis of resistance in Mycobacterium tuberculosis was analyzed and the susceptibility of mycobacterium to isoniazid was compared with its derivatives. The main emphasis was to compute the atomic and molecular interactions associated with the binding of antitubercular drugs with InhA, an enzyme involved in the biosynthesis of mycolic acids in Mycobacterium tuberculosis_. Fourteen ligand molecules were studied. The ligands were isoniazid and its derivatives and I-NADH. Molecular docking technique was used to generate the docked complexes of each ligand with InhA. In order to find the cause of resistance developed in mutant strains, the docked conformations of I-NADH were compared with the wild-type and the mutanttype InhA. The major structural difference found was the repositioning of adenine ring instead of its original position in the wild-type InhA that cause a decrease in affinity with phenylalanine 41 and an increased interactions from the mutant residue alanine 94, thus drifting from its ideal position. This drift in the position of phenylalanine 41 due to mutant alanine 94 may have altered the direction and position of isonicotinic acyl group attached to NADH at the other end facing amino acid phenylalanine 149. The study suggests that this particular change in the structure of I-NADH with respect to InhA could be the major cause of resistance developed in Mycobacterium tuberculosis. In the case of derivatives, INH14 (1-isonicotinyl-2-tetradecanoyl hydrazine) and INH16 (1- isonicotinyl-2-hexadecanoyl hydrazine) showed marked increase in binding affinity compared to isoniazid. Further studies on derivatives could prove useful in the design of a new generation of antitubercular drugs. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/1601 | |
| dc.subject | INTERACTIONS OF ISONIAZID AND ITS DERIVATIVES WITH MYCOBACTERIUM TUBERCULOSIS SUSCEPTIBLE ENZYME | en_US |
| dc.title | INTERACTIONS OF ISONIAZID AND ITS DERIVATIVES WITH MYCOBACTERIUM TUBERCULOSIS SUSCEPTIBLE ENZYME: MOLECULAR MODELING AND DOCKING STUDIES | en_US |
| dc.type | Thesis | en_US |
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