Screening and Structure-Activity Relationship of Potential Compounds against Proposed Targets of COVID-19 Infection

Abstract

Background: With reference to COVID-19 pandemic prevailing across the globe, chloroquine and hyrdoxycholoroquine were reported as effective against the disease to some extent. This effectiveness can be attributed to the glycosylation interruption of Angiotensin-converting enzyme 2 (ACE2) receptor which is a known target for SARS-CoV-2 entery. On the other hand, studies suggest that inhibition of ACE2 can prove to be lethal in certain cases thereby causing cardiovascular disorders, specially in patients already suffering from heart related diseases. Methods: In this study, most probable targets (other than ACE2) have been proposed for the treatment of COVID-19 infection by taking chloroquine and hydroxychloroquine as reference drugs. To achieve this objective, SwissTargetPrediction and PASSonline tools were used. Known drugs against each target possessing close relation to either viral infections or lung disorders were assessed from DrugBank database and simultaneous efficacy of these drugs towards other proposed targets were analyzed. By taking most effective drugs as reference, similar compounds were screened from ChEMBL library by using SwissSimilarity tool. Finally, molecular docking studies were performed through MOE software by using screened compounds against proposed targets. Results: Four most probable targets have been proposed including chemokine receptors (CCRs), dipeptidyl peptidase 4 (DPP4), muscarinic acetylcholine receptors (CHRMs) and histamine N-methyltransferase (HNMT). Furthermore, it has been evaluated that Quinacrine and vildagliptin are effective against most of the proposed targets. Taking vildagliptin and quinacrine as reference drugs, eight other similar compounds effective against these targets have been screened from ChEMBL library. Molecular docking studies with CCR5, DPP4 and CHRM5 suggested that quinacrine and its analogue (ChEMBL1782742) as well as vildagliptin and its analogue (ChEMBL511785) are the most suitable compounds hitting these targets. Conclusions: It has been established that quinacrine, ChEMBL1782742, vildagliptin, ChEMBL511785, mavorixafor, atropine, and N-(2-aminoethyl)-1-aziridineethanamine can be considered as effective in descending order for the treatment of COVID-19 infection.