Homology modelling, molecular docking, and molecular dynamics simulations reveal the inhibition of Leishmania donovani dihydrofolate reductase-thymidylate synthase enzyme by Withaferin-A

Abstract

ObjectivePresent in silico study was carried out to explore the mode of inhibition of Leishmania donovani dihydrofolate reductase-thymidylate synthase (Ld DHFR-TS) enzyme by Withaferin-A, a withanolide isolated from Withania somnifera. Withaferin-A (WA) is known for its profound multifaceted properties, but its antileishmanial activity is not well understood. The parasite’s DHFR-TS enzyme is diverse from its mammalian host and could be a potential drug target in parasites.ResultsA 3D model of Ld DHFR-TS enzyme was built and verified using Ramachandran plot and SAVES tools. The protein was docked with WA-the ligand, methotrexate (MTX)-competitive inhibitor of DHFR, and dihydrofolic acid (DHFA)-substrate for DHFR-TS. Molecular docking studies reveal that WA competes for active sites of both Hu DHFR and TS enzymes whereas it binds to a site other than active site in Ld DHFR-TS. Moreover, Lys 173 residue of DHFR-TS forms a H-bond with WA and has higher binding affinity to Ld DHFR-TS than Hu DHFR and Hu TS. The MD simulations confirmed the H-bonding interactions were stable. The binding energies of WA with Ld DHFR-TS were calculated using MM-PBSA. Homology modelling, molecular docking and MD simulations of Ld DHFR-TS revealed that WA could be a potential anti-leishmanial drug.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3354-1) contains supplementary material, which is available to authorized users.

<em>Leishmania</em> Proteomics: An <em>in Silico</em> Perspective

“…These salvage pathways are need for normal metabolic processes in Leishmania parasites, because theses microorganism are auxotrophics for folate compounds which are required in critical Leishmania metabolic pathways, including nucleic acid and protein biosynthesis. 44,45 The DHFR enzyme structure between hosts and parasites diverged extensively, which has permitted the synthesis of several specific DHFR inhibitors known as antifolates. 46 Dihydroorotate dehydrogenase (DHODH) (PDB ID: 3GYE) is a flavoprotein enzyme involved in the de novo pyrimidine biosynthesis pathway with other six catalytic proteins.…”

“…This reaction is essential for membrane cell biosynthesis, specifically, CYP51 relates to the ergosterol pathway, and is T. cruzi and T. brucei do not belong at the Leishmania protein group, but they have been used in some studies as homologous proteins. 45,73 Transferases group (EC. 2)…”

Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome

“…DNA topoisomerases that control the over-or underwinding of DNA have been reported as deadly targets for topoisomerase inhibitors that may act as potential antileishmanial drugs [25]. Computational tools using in silico approaches targeting key enzymes in metabolic pathways of Leishmania have led to identification of several potential druggable targets such as cytochrome P450 sterol 14α-demethylase [26], dihydrofolate reductase-thymidylate synthase [27], methylglyoxal degradation superpathway [28], trypanothione reductase [29]. Trypanothione reductase is absent in humans and neutralizes the reactive oxygen species generated inside the infected macrophages.…”

Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase

“…For case in which the atomic structures of enzyme macromolecules are absent, homology modeling is a powerful tool to understand the general fold of the enzyme, catalytic site, and conserved residues, in addition to the substrate and inhibitor binding sites. This information is crucial for structure-based drug design approaches for the development of potential enzyme inhibitors for therapeutic application [19]. In addition, waldiomycin and its methyl ester analog, produced by Streptomyces sp., were reported as inhibitors of S. aureus HK with IC 50 values of 10.2 and 75.8 μM, respectively, and are effective as antibacterial agents against S. aureus species [20].…”