Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives

Abstract

Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 ( P value < 0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r = 0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.

Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants

“…The diversity of targets and mechanisms of action of plant 1,4-NQs have stimulated great pharmacological interest, particularly in the area of ROS initiation and signaling, cancer therapeutic strategies and as anti-inflammatory agents. 214 , 286 Moreover, numerous analogs of 1,4-NQs have been designed and synthesized to enhance their toxicity toward specific human cancer cell lines, 277 , 287–289 specific proteins (for example, Hsp90), 290 selected pathogenic organisms (for example, Trypanosoma sp) 291–293 and insects. 294…”

Molecular Docking Studies on Anticonvulsant Enaminones Inhibiting Voltage-Gated Sodium Channels

“…The resulting poses with higher binding scores are the poses most likely to be preferred by the ligand docked in the pockets. A total of 30 top-score docking poses were constructed and the best scoring complex of the ligand in a specific site was selected for further analysis[23].…”

Translating Chagasic dilating cardiomyopathy to surgical therapies: An under published global challenge

“…ChHF offers a so far neglected translational model of parasymphatholytic rhythm-driven (early right bundle branch block (RBBB), left anterior fascicular block (LAFB), or other less common dysrhythmias 15,20 ), and eventually non-ischemic cardiac failure, with occasional pulmonary hypertension. 21 Trypanostatic pharmacology 22,23 is evolving and is intertwined with intensive care, new diagnostics, and changing epidemiology, 24–26 as the disease knows no geographical barriers. 27 We could all translate any lessons thus learned to global perioperative healthcare.…”