Determination of binding affinities of some approved drugs to Ascaris suum mitochondrial rhodoquinol-fumarate reductase by in silico molecular docking

Abstract

The binding affinity of a drug for a receptor describes how avidly the drug binds to the receptor. Drugreceptor binding determines the ability to produce a pharmacological response and to some extent the size of that response. The study investigated the binding affinities of some approved drugs to Ascaris suum mitochondrial rhodoquinol-fumarate reductase(MRFR), an essential Ascaris enzyme, by in silico molecular docking simulations. Twenty eight approved drugs were carefully selected based on the possibility of their pharmacological action on Ascaris smooth muscles or antiparasitic activities. Selected drugs were obtained from ZINC^® database as mol2 files and further prepared for docking simulations using AutoDock tools v. 1.5.6. Ascaris MRFR was obtained as pdb file (3vra) from the Protein Data Bank and further prepared for docking simulations using both Chimera v. 1.8.1 and AutoDock tools v. 1.5.6. In order to validate the docking protocol, the binding of atpenin, an experimental anthelmintic compound, to MRFR was successfully reproduced in silico. Docking simulations were performed using AutoDockVina 4.0 on a Linux platform. Docking results were analyzed using PyMol v.0.99r c6. Molecular dynamics was employed for the validation of complexed frontrunner approved drugs. Binding free energies of -8.60, -7.75 and -7.50 kcal/mol were obtained for atovaquone, carvedilol and atpenin respectively. Zero binding free energies were recorded for tinidazole, piperazine, bithionol, thiabendazole and metronidazole. Molecular dynamics simulations of atovaquone and carvedilol complexed with the reductase enzyme revealed a strongly favourable binding with likely favourable entropic term in the case of carvedilol. Atovaquone and carvedilol were thus predicted as frontrunner approved drugs with possible anthelmintic activities comparable to atpenin. In vitro and in vivo investigations into the anthelmintic activities of atovaquone and carvedilol are recommended.

Key-words: Ascaris, docking, molecular dynamics, anthelmintics, drug repurposing.