Editor-in-Chief Hatice Kübra Elçioğlu Vice Editors Levent Kabasakal Esra Tatar Online ISSN 2630-6344 Publisher Marmara University Frequency Bimonthly (Six issues / year) Abbreviation J.Res.Pharm. Former Name Marmara Pharmaceutical Journal
Journal of Research in Pharmacy 2021 , Vol 25 , Issue 6
Pyrazine-chromene-3-carbohydrazide conjugates: Molecular docking and ADMET predictions on dual-acting compounds against SARS-CoV-2 Mpro and RdRp
Arif MERMER1,Serhii VAKAL2
1Experimental Medicine Research and Application Center, University of Health Sciences-Turkey, 34660, Turkey
2Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland DOI : 10.29228/jrp.92 Drug discovery campaigns against COVID-19 lag far behind vaccine development, but given the low vaccine production rate and unfair distribution, there is still an urgent need to advance reliable and potent anti-SARS-CoV-2 agents. We aimed to identify novel and effective molecules with dual-target activity against SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA-polymerase (RdRp). For this, we designed and evaluated the library of hybrid compounds based on pyrazine and 4H-chromen-4-one linked by amide bridges. The synthetic availability of the compounds ranged from 3.08 to 3.40, indicating that these compounds are easy to synthesize. According to in silico ADMET prediction, most of the compounds satisfied all rules of drug-likeness. Compounds CPC-2, 3, 4, 8, 10, 11-14, and 16 were CYP1A2, CYP2C9, and CYP3A4 inhibitors, whereas none of them inhibited CYP2C19 and CYP2D6 isoforms. All designed compounds were predicted to be well-absorbed in the GI tract but not blood-brain barrier permeant and not subject to active efflux.

Molecular docking studies against SARS-CoV-2 Mpro showed that compounds CPC-1, 6, 7, 8, and 10 could establish multiple H-bonds with the binding site residues. In the case of SARS-CoV-2 RdRp, compounds CPC-5, 6, 8, 13, 14, and 16 had the most favorable binding orientations and could establish H-bonds, pi-cation, and salt-bridges with the binding tunnel residues and RNA. Compound CPC-6 turned to be the most promising candidate from the dual-action side since it had reasonable docking scores and MM-GBSA ΔGbind values, and good interaction profiles for both Mpro and RdRp. Keywords : Pyrazine; chromen-4-one; ADMET; molecular docking; SARS-CoV-2 Mpro; SARS-CoV-2 RdRp

Marmara University