Calendulaglycoside A showing potential activity against SARS-CoV-2 main protease: Molecular docking, molecular dynamics, and SAR studies

Abstract

Background and Aim The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, natural products can provide therapeutic alternatives that could be employed as an effective safe treatment for COVID-19. Experimental procedure Twelve compounds were isolated from the aerial parts of C. officinalis L. and investigated for their inhibitory activities against SARS-CoV-2 M pro compared to its co-crystallized N3 inhibitor using molecular docking studies. Furthermore, a 100 ns MD simulation was performed for the most active two promising compounds, Calendulaglycoside A (SAP5) and Osteosaponin-I (SAP8). Results and Conclusion At first, molecular docking studies showed interesting binding scores as compared to the N3 inhibitor. Calendulaglycoside A (SAP5) achieved a superior binding than the co-crystallized inhibitor indicating promising affinity and intrinsic activity towards the M pro of SARS-CoV-2 as well. Moreover, findings illustrated preferential stability for SAP5 within the M pro pocket over that of N3 beyond the 40 ns MD simulation course. Structural preferentiality for triterpene-M pro binding highlights the significant role of 17 β -glucosyl and carboxylic 3 α -galactosyl I moieties through high electrostatic interactions across the MD simulation trajectories. Furthermore, this study clarified a promising SAR responsible for the antiviral activity against the SARS-CoV-2 M pro and the design of new drug candidates targeting it as well. The above findings could be promising for fast examining the previously isolated triterpenes both pre-clinically and clinically for the treatment of COVID-19.

Anti-SARS-CoV-2 activities of tanshinone IIA, carnosic acid, rosmarinic acid, salvianolic acid, baicalein, and glycyrrhetinic acid between computational and in vitro insights

“…However, salvianolic acid (4) showed a weak anti-SARS-CoV-2 activity with an IC 50 value of 58.29 ng ml À1 . Moreover, the mode of action for the most two promising compounds, tanshinone IIA (1) and carnosic acid (2), to understand the mechanism of their antiviral activity towards SARS-CoV-2 showed a very promising virucidal activity for both compounds with a most prominent inhibitory effect on the viral adsorption rather than its replication. This claries the predicted activity of the two compounds against the S protein of SARS-CoV-2 rather than its Mpro protein.…”

“…The MolSA showed initial uctuations from the start of the simulation till reaching its equilibrium at 10 ns and was returned to uctuations again at 50 ns till the end of the simulation time. Its range was observed in between (525-620Å 2 ) with an equilibrium around 600Å 2 . Moreover, the SASA of salvianolic acid showed moderate uctuations throughout the simulation time, its range was between 300 to 800Å 2 , and the equilibrium was around 500Å 2 .…”

“…53 2.1.3. Docking of the prepared compounds (1)(2)(3)(4)(5)(6) to the viral spike and main protease pockets. At the start, to validate the docking process of the MOE program and ensure its accuracy, we performed a redocking process for the N3 cocrystallized inhibitor of Mpro enzyme, and a valid performance of the program was conrmed by obtaining a low value of RMSD (1.23Å).…”

“…1 It has been named coronavirus disease 19 (COVID- 19), which is known for its high infectivity and pathogenicity, and its causative virus was named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). 2 Coronaviruses generally infect the lower respiratory tract and their spike proteins are critical for host cell entry, 3 because of highly mutated spikes there is an urgent need for safe and effective drugs by nding a new broad-spectrum anticoronavirus candidate, such as spike protein inhibitors that halting the fusion of the spike (S) protein of coronaviruses and angiotensin-converting enzyme 2 (ACE2) of the host. 4 Scientists have been screened for new compounds from medicinal plants to avert the COVID-19 global crisis, 5 it could be through halting the activity of enzymes associated with the virus replication cycle, including 3C-like protease (3CLpro) and papain-like protease (PLpro), and also inhibit cellular signaling pathways to prevent COVID-19 or at least to relieve its deadly symptoms.…”

Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

“…Intestinal absorption is defined as the percentage absorbed of a compound from the gut wall (Mannhold et al, 2012;Zaki et al, 2021). A well-absorbed compound can penetrate the bloodstream in humans by at least 90% (Klopman et al, 2002).…”