Pharmacoinformatic study of inhibitory potentials of selected flavonoids against papain-like protease and 3-chymotrypsin-like protease of SARS-CoV-2

Abstract

Background Inhibition of papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is projected to terminate its replication. Hence, these proteases represent viable therapeutic targets. Methods Sixty-one flavonoids with reported activities against other RNA viruses were selected and docked in PLpro and 3CLpro. Flavonoids with better binding energies compared to reference inhibitors (lopinavir and ritonavir) in their interaction with PLpro and 3CLpro were selected for drug-likeness and ADMET analysis. The best representative flavonoid for each protease from the ADMET filtering analysis was subjected to molecular dynamics simulations (MDS) and clustering analysis of the trajectory files. Results Licorice, ugonin M, procyanidin, silymarin, and gallocatechin gallate had better binding energies (-11.8, -10.1, -9.8, -9.7 and -9.6 kcal/mol respectively) with PLpro compared to lopinavir and ritonavir (-9.1 and -8.5 kcal/mol respectively). Also, isonymphaeol B, baicalin, abyssinone II, tomentin A, and apigetrin had better binding energies (-8.7, -8.3, -8.2, -8.1, and -8.1 kcal/mol respectively) with 3CLpro compared to lopinavir and ritonavir (-7.3 and -7.1 kcal/mol respectively). These flavonoids interacted with the proteases via hydrogen and non-hydrogen bonding. Of these flavonoids, silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics in silico. These two flavonoids exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run. Conclusion Silymarin and isonymphaeol B are proposed for further studies as compounds with potential activities against SARS-CoV-2.

Chymotrypsin, Urease Inhibitory and Antioxidant Activities of Malva neglecta Wallr.

“…7,[11][12][13] Yakın zamanda pandemiye neden olan SARS-COV-2 enfeksiyonu başta olmak üzere farklı hastalıklar üzerindeki araştırmalarda da bu enzime odaklanılmıştır. 12,[14][15] Klinik kullanımına izin verilen bir adet kimotripsin inhibitörü bulunmaktadır. Ulinastatin® jenerik adı ile piyasaya sürülen bu ürün akut-kronik pankreatit, Stevens-Johnson sendromu, yanık, septik şok ve toksik epidermal nekrolizis gibi durumlara endike olmakla birlikte yan etkileri bulunmakta ve intravenöz yoldan uygulanabilmektedir.…”