In silico and In vitro Investigations of Antihelmintic Activities of some Selected Approved Drugs
Authors: Agube Christopher Arinze , Ajaghaku Daniel Lotanna , Uzochukwu Ikemefuna Chijioke 
Published: November 2019

AbstractThe search for alternative methods to mitigate the drawbacks associated with wet laboratory drug discovery has been a major challenge in drug design and has limited the options available in the fight against most Neglected Tropical Diseases (NTDs) such as helminthiasis. We investigated the binding affinities of some approved drugs to Ascaris suum mitochondrial rhodoquinol fumarate reductase enzyme (MRFR),an essential enzyme for ascaris survival, and the possibility of repurposing these drugs as antihelmintic agents using in silico molecular docking and in vitro paralysis and mortality times of fifteen selected front runners.Two hundred approved drugs were selected from ZINC® database based on bioactivity scores while MRFR(PDB code, 3vra) was obtained from the Protein Data Bank (PDB). Both were prepared using AutoDock tools v.1.5.6 and Chimerav.1.9.The docking protocol was validated by computationally reproducing the binding of atpenin to MRFR. The selected approved drugs and the receptor were docked using AutoDockVina v. 4.0. The docking results were analyzed using PyMoL v. 1.4.1.The paralysis and mortality times of the identified frontrunners against Pheretima posthuma were determined in vitro and synergistic testings were done by the checkerboard method. Fifteen drugs had binding free energies between −7.825 to 11.025 kcal/mol while four of these drugs (mefloquine, doxycycline, mepacrine and proguanil) emerged as major frontrunners by both in silico and in vitro assessments. The paralysis and mortality times of the four drugs were between 0.33-0.50 hr as against 1.80-2.36 hr for albendazole. They were therefore predicted to have ability to affect MRFR in the same manner as atpenin hence, suggestive of potential antihelmintic activity. In vivo investigation of these frontrunner drugs is strongly recommended.Author SummaryFor decades, intestinal worm infections have been a major public health problem particularly in the tropical regions of the world with infection figures put at 5.3b [16].This disease is often associated with poor hygiene and sanitation hence is predominant in the resource-poor nations with physical infrastructural deficit [8].Children between the ages of 2-10 years are the most vulnerable by reason of their hand habits with morbidity leading to compromise of physical and cognitive development while several sufferers have had to live disability-adjusted life years as a consequence [12].Efforts at implementing improved hygiene and mass deworming campaigns have not delivered the intended outcomes with many reports coming from clinicians regarding gradual development of resistance to the standard treatments [9].Given the huge cost and time invested in traditional drug discovery and the rarity of this disease in regions of the world with the resources for research, no new drugs have been developed in the past two decades [18].The advent of computational techniques in drug discovery has come to mitigate these drawbacks. This study exploited this technique to full effect and through laboratory assays and clinical investigation of selected approved drugs, mepacrine and doxycycline were identified as potential antihelmintic agents fit for combination therapy.