@article{25969,
  keywords = {Binding affinities, Dapsone, Dihydropteroate Synthase, Drug Resistance, Molecular Docking, Multidrug therapy, Point Mutations},
  author = {Chaitanya SV and Das M and Bhat P and Ebenezer M},
  title = {Computational Modelling of Dapsone Interaction with Dihydropteroate Synthase in Mycobacterium leprae; Insights into Molecular Basis of Dapsone Resistance in Leprosy.},
  abstract = {<p>The Molecular basis for determination of resistance to anti-leprosy drugs is the presence of point mutations within the genes of Mycobacterium leprae (M. leprae) that encode active drug targets. The downstream structural and functional implications of these point mutations on drug targets were scarcely studied. In this study, we utilized computational tools to develop native and mutant protein models for 5 point mutations at codon positions 53 and 55 in 6-hydroxymethyl-7, 8-dihydropteroate synthase of M. leprae, an active target for dapsone encoded by folp1 gene, that confer resistance to dapsone. Molecular docking was performed to identify variations in dapsone interaction with mutant 6-hydroxymethyl-7, 8-dihydropteroate synthase in terms of hydrogen bonding, hydrophobic interactions and energy changes. Schrodinger Suite 2014-3 was used to build homology models and in molecular docking. An increase in volume of the binding cavities of mutant structures was noted when compared to native form, indicating a weakening in interaction (60.7Å(3) in native vs. 233.6Å(3) in Thr53Ala, 659.9Å(3) in Thr53Ile, 400Å(3) for Thr53Val, 385Å(3) for Pro55Arg and 210Å(3) for Pro55Leu). This was also reflected by changes in hydrogen bonds and decrease in hydrophobic interactions in the mutant models. The total binding energy (ΔG) decreased significantly in mutant forms when compared to the native form (-51.92 Kcal/mol for native Vs. -35.64 Kcal/mol, -35.24 Kcal/mol, -46.47 Kcal/mol, -47.69 Kcal/mol and -41.36 Kcal/mol for mutations Thr53Ala, Thr53Ile, Thr53Val, Pro55Arg and Pro55Leu respectively. In brief, this analysis provided structural and mechanistic insights to the degree of dapsone resistance contributed by each of these DHPS mutants in leprosy. This article is protected by copyright. All rights reserved.</p>
},
  year = {2015},
  journal = {Journal of cellular biochemistry},
  issn = {1097-4644},
  doi = {10.1002/jcb.25180},
  language = {eng},
}