Ul-Haq (2020): Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach, Journal of Biomolecular Structure and Dynamics, ABSTRACT Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CL pro ) in viral replication and maturation turns it into an attractive target for the development of effective antiviral drugs against SARS and other coronaviruses. At present, there is no standard drug regime nor any vaccine available against the infection. The rapid development and identification of efficient interventions against SARS-CoV-2 remains a major challenge. Based on the available knowledge of closely related coronavirus and their safety profiles, repurposing of existing antiviral drugs and screening of available databases is considered a near term strategic and economic way to contain the SARS-CoV-2 pandemic. Herein, we applied computational drug design methods to identify Chymotrypsin-like protease inhibitors from FDA approved antiviral drugs and our in-house database of natural and drug-like compounds of synthetic origin. As a result three FDA approved drugs (Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CL pro ) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.

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The aim of this investigation was to see if the crude extract of Sarcococca saligna (Ss.Cr) contains chemicals with gut function inhibitory activity by using in vitro and in vivo assays. Ss.Cr caused a dose-dependent (0.03 - 3 mg/mL) inhibitory effect on K+-induced contractions in rat stomach fundus, guinea-pig ileum and rabbit jejunum preparations. The calcium channel blocking(CCB) activity was confirmed when Ss.Cr caused a rightward shift in the Ca++ dose-response curves. It also potentiated, at lower do-ses (0.001 - 0.03 mg/mL), the contractile effect of a fixed dose of acetylcholine (ACh), similar to physostigmine, and suppressed the effect of ACh at higher doses (0.3 - 1.0 mg/mL). Both Ss.Cr and physostigmine inhibited acetylcholinesterase (AChE), in the in vitro assay, confirming the AChE inhibitory activity. In the in vivo studies, Ss.Cr exhibited antidiarrheal and antisecretory activities against castor oil-induced diarrhea and intestinal fluid accumulation in mice. Characteristic steroidal compounds of the plant (saracocine, saracodine, saracorine and alkaloid-C), exhibited a similar combination of AChE inhibitory and CCB activities. Thus this study provides a sound mechanistic base for some of the traditional uses of the plant in hyperactive gut states, in addition to providing the first evidence for verapamil to possess additional AChE inhibitory activity. Furthermore, these characteristic compounds with dual activity may be good candidates for further studies on their usefulness in Alzheimer's disease.