Molecular modeling and chemical modification for finding peptide inhibitor against severe acute respiratory syndrome coronavirus main proteinase Qishi Du a,e, * , Shuqing Wang a , Dongqing Wei a,b,e, * , Suzanne Sirois b,c,d,e , Kuo-Chen Chou a,d, * a Tianjin Institute of Bioinformatics and Drug Discovery, Tianjin Normal University, Tianjin 300074, China b Center for Research in Molecular Modeling (CERMM), Concordia University, Montreal, Canada c Universite ´ du Que ´bec a ` Montre ´al (UQAM) Chemistry Department, C.P. 8888, succursale Centre-Ville, Montreal, Que., Canada H3C 3P8 d Immune Deficiency Treatment Center (IDTC), Montreal General Hospital, McGill University Health Center, 1650 Cedar Avenue, Montre ´al, Que ´bec, H36 1A4, Canada e Gordon Life Science Institute, San Diego, CA 92130, USA Received 28 August 2004 Available online 23 December 2004 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 (M pro or 3CL pro ) on the octapeptide NH 2 - AVLQ fl SGFR-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 p 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. N d1 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 CH 2 or CF 2 or changing the NH of Ser to CH 2 or CF 2 . The octapeptide thus modified might become an effective inhibitor or a potential drug candidate against SARS. Ó 2004 Elsevier Inc. All rights reserved. Keywords: SARS; SARS CoV M pro ; Inhibitor; Drug design; ‘‘Distorted key’’ theory A new coronavirus (SARS CoV) 1 has been found as the etiological agent of the disease SARS [1–4]. SARS CoV is a positive-sense, single-stranded RNA virus with the largest viral RNA genome known to date [5,6]. The SARS CoV genome is composed of around 29,700 nucleotides. The replicase gene alone encompasses more than 21,000 nucleotides, 2/3 of the whole genome se- quence. The replicase gene encodes two overlapping polyproteins, pp1a (4377 a.a.) and pp1ab (7072 a.a.). SARS CoV main proteinase (M pro ) cleaves the polypro- tein at no less than 11 conserved sites, a process initiated by the enzymeÕs own autolytic cleavage from pp1a and pp1ab [7,8]. The released polypeptides mediate all of the functions required for SARS viral replication and transcription. The functional importance of the M pro 0003-2697/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ab.2004.10.003 * Corresponding author. E-mail addresses: duqishi@yahoo.com (Q. Du), dqwei_2000@ yahoo.com (D. Wei), kchou@san.rr.com (K.-C. Chou). 1 Abbreviations used: SARS CoV, severe acute respiratory syndrome coronavirus; a.a., amino acids; M pro , main proteinase. www.elsevier.com/locate/yabio Analytical Biochemistry 337 (2005) 262–270 ANALYTICAL BIOCHEMISTRY