title: Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase.
abstract: Severe acute respiratory syndrome (SARS) is a respiratory disease caused by a newly found virus, called SARS coronavirus. In this study, the cleavage mechanism of the SARS coronavirus main proteinase (Mpro or 3CLpro) on the octapeptide NH2-AVLQ downward arrowSGFR-COOH was investigated using molecular mechanics and quantum mechanics simulations based on the experimental structure of the proteinase. It has been observed that the catalytic dyad (His-41/Cys-145) site between domains I and II attracts the pi electron density from the peptide bond Gln-Ser, increasing the positive charge on C(CO) of Gln and the negative charge on N(NH) of Ser, so as to weaken the Gln-Ser peptide bond. The catalytic functional group is the imidazole group of His-41 and the S in Cys-145. Ndelta1 on the imidazole ring plays the acid-base catalytic role. Based on the "distorted key theory" [K.C. Chou, Anal. Biochem. 233 (1996) 1-14], the possibility to convert the octapeptide to a competent inhibitor has been studied. It has been found that the chemical bond between Gln and Ser will become much stronger and no longer cleavable by the SARS enzyme after either changing the carbonyl group CO of Gln to CH2 or CF2 or changing the NH of Ser to CH2 or CF2. The octapeptide thus modified might become an effective inhibitor or a potential drug candidate against SARS.
authors.affiliation: Tianjin Institute of Bioinformatics and Drug Discovery, Tianjin Normal University, Tianjin 300074, China. duqishi@yahoo.com
authors.forename: Qishi
authors.initials: Q
authors.lastname: Du
authors.forename: Shuqing
authors.initials: S
authors.lastname: Wang
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wei
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sirois
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
mesh_terms: D000208:Acute Disease; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy* / Q000821:virology
chemical_list: D004791:Enzyme Inhibitors; D010447:Peptide Hydrolases