ABSTRACT
Objective: To identify potential SARS-CoV-2 3CL protease inhibitors from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) by molecular docking approach. Methods: To alternate extensive compounds experimental screening processes, a Computer-Aided Drug Design (CADD) based molecular docking technology was performed to explore existing drug repurposing possibilities. Molecular docking model with Schrodinger suit 2018 was used to evaluate the binding abilities between TCMSP 13 143 compounds and SARS-CoV-2 3CL protease receptor-binding domain (PBD ID 6LU7), which involving in mediating viral replication and transcription functions. According to the constructed docking system, potential compounds were screened according to docking score, oral bioavailability (OB), and drug-likeness (DL). At last, a compounds-herb-target organ-function network was constructed. Results: Compared with 6LU7 original ligand docking score (-7.734), a total of 498 compounds were identified with lower docking score against 6LU7 targets. These compounds were further reduced to 60 high-priority compounds, based on OB (more than 30) and DL (more than 0.18). Meanwhile, these 60 compounds were found to interact with the amino acid residues (GLU166, GLY143, ASP187, CYS145, GLN189, LEU141, etc.) which were critically involved in the 6LU7 domain mainly by hydrogen-bonded interaction. The network exploring results revealed that these potential compounds were mainly attributed to Glycyrrhizae Radix et Rhizoma, Mori Cortex, Rhododendron dauricum, Polygoni Cuspidati Rhizoma et Radix, and Plantaginis Herba, etc., which associates with acute lung syndromes induced by SARS-CoV-2, with the effect of clearing heat and removing toxin, relieving cough and dispelling phlegm and lung-draining and relieving asthma. Conclusion: Molecular docking method provides a useful tool for the screening of SARS-CoV-2 3CL protease inhibitors from TCMSP platform.
ABSTRACT
Picornaviruses(PV)and coronaviruses(CoV) are positive-stranded RNA viruses. Pathogens in the family can cause hand,foot and mouth disease,myocarditis, common cold ,severe respiratory and intestinal diseases. 3C and 3CL proteases, belonging to cysteine proteases,are required to process polyproteins into mature proteins for viral replication,which plays an impor?tant role in viral replication because substrate binding sites are highly conservative and have similar catalytic mechanism. 3C and 3CL proteases are different from protease in the human body ,which represents a promising anti-viral drug target. Using 3C and 3CL pro?teinase structural similarities,broad spectrum protease inhibitors have been found successfully. This review describes recent develop?ments of broad spectrum protease inhibitors targeting on 3C and 3CL proteases,and briefly illustrates the mechanism of the inhibitors, which may benefit to the development of virus therapy.
ABSTRACT
Picornaviruses (PV) and coronaviruses (CoV) are positive-stranded RNA viruses. Pathogens in the family can cause hand, foot and mouth disease, myocarditis, common cold, severe respiratory and intestinal diseases. 3C and 3CL proteases, belonging to cysteine proteases, are required to process polyproteins into mature proteins for viral replication, which plays an important role in viral replication because substrate binding sites are highly conservative and have similar catalytic mechanism. 3C and 3CL proteases are different from protease in the human body, which represents a promising anti-viral drug target. Using 3C and 3CL proteinase structural similarities, broad spectrum protease inhibitors have been found successfully. This review describes recent developments of broad spectrum protease inhibitors targeting on 3C and 3CL proteases, and briefly illustrates the mechanism of the inhibitors, which may benefit to the development of virus therapy.