title: Computational Modelling of Dapsone Interaction With Dihydropteroate Synthase in Mycobacterium leprae; Insights Into Molecular Basis of Dapsone Resistance in Leprosy.
abstract: 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 (DHPS) 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 DHPS in terms of hydrogen bonding, hydrophobic interactions, and energy changes. Schrodinger Suite 2014-3 was used to build homology models and in performing 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 (60.7 Å(3) in native vs. 233.6 Å(3) in Thr53Ala, 659.9 Å(3) in Thr53Ile, 400 Å(3) for Thr53Val, 385 Å(3) for Pro55Arg, and 210 Å(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, -35.24, -46.47, -47.69, 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.
authors.affiliation: Research Officer, Department of Laboratories, Molecular Biology and Immunology Division, The Schieffelin Institute of Health-Research and Leprosy Center (SIH-R&LC), Karigiri, Vellore, Tamil Nadu, 632106, India.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Chaitanya V
authors.affiliation: Research Officer, Department of Laboratories, Molecular Biology and Immunology Division, The Schieffelin Institute of Health-Research and Leprosy Center (SIH-R&LC), Karigiri, Vellore, Tamil Nadu, 632106, India.
authors.forename: Madhusmita
authors.initials: M
authors.lastname: Das
authors.affiliation: Applications Scientist, Schrodinger, Inc., Near KMWA Vidya Niketan, Mahalakshmipuram, Bangalore, 560 086, India.
authors.forename: Pritesh
authors.initials: P
authors.lastname: Bhat
authors.affiliation: The Schieffelin Institute of Health-Research and Leprosy Center (SIH-R&LC), Karigiri, Vellore, Tamil Nadu, 632106, India.
authors.forename: Mannam
authors.initials: M
authors.lastname: Ebenezer
mesh_terms: D003622:Dapsone / Q000008:administration & dosage*; D004094:Dihydropteroate Synthase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D007918:Leprosy / Q000188:drug therapy / Q000235:genetics*; D062105:Molecular Docking Simulation; D009166:Mycobacterium leprae / Q000187:drug effects* / Q000472:pathogenicity; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D003622:Dapsone; D004094:Dihydropteroate Synthase
keywords: BINDING AFFINITIES; DAPSONE; DIHYDROPTEROATE SYNTHASE; DRUG RESISTANCE; MOLECULAR DOCKING; MULTIDRUG THERAPY; POINT MUTATIONS