Alanine scanning of dinitroaniline/phosphorothioamidate site of α-tubulin in plasmodium species distributed in India

Abstract

Aim. Identification of amino acid residues participating in specific binding of dinitroaniline and phosphorothioamidate compounds with α-tubulin in Plasmodium falciparum. Methods. Protein structure modelling, protein structure optimization using molecular dynamics method, ligand-protein docking, alanine scanning mutagenesis. Results. Molecular docking of canonical compounds and alanine scanning mutagenesis, indicate two key (Arg2, Val250) and one minor (Glu3) residues involved in binding of both - dinitroaniline and phosphorothioamidate compounds. At the same time, it was revealed two minor residues (Asp251, Glu254) interacting only with some members of dinitroaniline grope. Conclusions. It was identified amino acid residues predetermining existence of joint site and similar interaction of α-tubulin with dinitroani-line and phosphorothioamidate compounds in P. falciparum.
 Keywords: malaria, Plasmodium, α-tubulin, molecular interaction, dinitroanilines compounds, phosphorothioamidate compounds, alanine scanning mutagenesis.

Atomic Resolution Homology Models and Molecular Dynamics Simulations of Plasmodium falciparum Tubulins

“…From the interactive site analysis, it was evident that the α1-, α2-, β-, and γ-tubulins of P. falciparum were sharing a common binding pocket with amino acid residues Gln11, Ala12, Ile14, Gln91, Leu92, Ala100, Thr143, Gly144, Tyr179, Ala180, and Arg228 with the presence of GTP and GDP (Figures S8−S10). A recent study has shown that residues Arg2, Gln133, Arg243, Asn249, Val250, Asp251, Val252, Thr253, and Glu254 are parasite α-tubulin-specific, 17 and a detailed comparative analysis of the four tubulin proteins with human tubulins revealed that Leu92 and Arg228 are found to be parasite-specific, which were lying around the same active region. Additionally, we found that the amino acid residues Ala12, Ile14, Gln91, Ala100, Tyr179, and Ala180 present in α1-, α2-, and β-tubulins are parasite-specific too.…”

“…A recent study has identified a parasite-specific binding site in Plasmodium α-tubulin, similar to plant α-tubulin but absent in human α-tubulin. , Recent advancements in structural bioinformatics, especially the methods based on comparative modeling, active site analysis, and protein simulations, have significantly progressed, which even facilitate the discovery of sites specific to a group of proteins . A potential target must be essential for the pathogen, and further designing of inhibitors should hinder the function exclusively to pathogen and should avoid the undesirable cross-reactivity with the human proteins.…”