title: Inhibition of Mycobacterium-RmlA by Molecular Modeling, Dynamics Simulation, and Docking.
abstract: The increasing resistance to anti-tb drugs has enforced strategies for finding new drug targets against Mycobacterium tuberculosis (Mtb). In recent years enzymes associated with the rhamnose pathway in Mtb have attracted attention as drug targets. The present work is on α-D-glucose-1-phosphate thymidylyltransferase (RmlA), the first enzyme involved in the biosynthesis of L-rhamnose, of Mtb cell wall. This study aims to derive a 3D structure of RmlA by using a comparative modeling approach. Structural refinement and energy minimization of the built model have been done with molecular dynamics. The reliability assessment of the built model was carried out with various protein checking tools such as Procheck, Whatif, ProsA, Errat, and Verify 3D. The obtained model investigates the relation between the structure and function. Molecular docking interactions of Mtb-RmlA with modified EMB (ethambutol) ligands and natural substrate have revealed specific key residues Arg13, Lys23, Asn109, and Thr223 which play an important role in ligand binding and selection. Compared to all EMB ligands, EMB-1 has shown better interaction with Mtb-RmlA model. The information thus discussed above will be useful for the rational design of safe and effective inhibitors specific to RmlA enzyme pertaining to the treatment of tuberculosis.
authors.affiliation: Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515 003, India.
authors.forename: N
authors.initials: N
authors.lastname: Harathi
authors.affiliation: Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515 003, India.
authors.forename: Madhusudana
authors.initials: M
authors.lastname: Pulaganti
authors.affiliation: Department of Biotechnology, Sri Krishnadevaraya University, Anantapur 515 003, India.
authors.forename: C M
authors.initials: CM
authors.lastname: Anuradha
authors.affiliation: Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515 003, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar Chitta