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