Structure-based virtual screening against SARS-3CLpro to identify novel non-peptidic hits

Abstract

Severe acute respiratory syndrome is a highly infectious upper respiratory tract disease caused by SARS-CoV, a previously unidentified human coronavirus. SARS-3CL(pro) is a viral cysteine protease critical to the pathogen's life cycle and hence a therapeutic target of importance. The recently elucidated crystal structures of this enzyme provide an opportunity for the discovery of inhibitors through rational drug design. In the current study, Gold docking program was utilized to conduct extensive docking studies against the target crystal structure to develop a robust and predictive docking protocol. The validated docking protocol was used to conduct a structure-based virtual screening of the Asinex Platinum collection. Biological evaluation of a screened selection of compounds was carried out to identify novel inhibitors of the viral protease.

Combined Virtual Screening Strategies

“…An alternative, increasingly popular strategy is the use of several fast computational techniques first, yielding an enriched, focused subset of compounds that are then docked through more accurate, computationally demanding tools. Mukherjee et al have implemented a 3-stage cascade docking aimed to the selection of the Chymotrypsin-like cysteine protease of SARS coronavirus, looking for just shape complementarity at the early stages and focusing on binding site interactions and geometrical quality of the binding pose later [63]. Departing from Asinex Platinum collection (120,000 compounds) they performed a pre-filtration with ADME filters retaining only 32,000 compounds.…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…Besides, several groups have identified a number of inhibitors of 3CLpro using a variety of approaches. Virtual screening (Plewczynski et al, 2007;Mukherjee et al, 2008;Nguyen et al, 2011) or a high-throughput screening of small molecule libraries have identified inhibitorsincluding an anti-HIV agent and serotonin antagonist, cinanserin (Blanchard et al, 2004;Kao et al, 2004;Wu et al, 2004a;Chen et al, 2005). Other 3CL protease inhibitors identified so far belongto categories such as plant derived phenolic or flavonoid compounds (Lin et al, 2005;Nguyen et al, 2012), active site, nonactive site or competitive inhibitors (Kaeppler et al, 2005;Lee et al, 2005;Du et al, 2007;Ryu et al, 2010), ketones or ester based inhibitors (Goetz et al, 2007;Zhang et al, 2007;Ghosh et al, 2008;Shao et al, 2008;Verschueren et al, 2008;Zhang et al, 2008), modified peptidomimetic inhibitors (Ghosh et al, 2007), metal conjugated inhibitors (Lee et al, 2007;…”

SARS coronavirus main proteinase 3.4.22.69

“…It can form a new type of dimer which is inactive. Therefore, the N-finger of SARS-CoV Mpro is not only cri-tical for its dimerization but also essential for the enzyme to form the enzymatically active dimer [40]) [26,40] Application analysis <2> (<2> developing a novel red-shifted fluorescence-based assay for 3CLpro and its application for identifying small-molecule anti-SARS agents from marine organisms [8]) [8] medicine <2> (<2> SARS-3CLpro is a viral cysteine protease critical to the life cycle of the pathogen and hence a therapeutic target of importance [29]; <2> this enzyme is a target for the design of potential anti-SARS drugs [28]) [28,29] 6 Stability Temperature stability 61 <2> (<2> Tm-value, sigmoid denaturation curve [27]) [27] Organic solvent stability guanidine-HCl <2> (<2> dimeric enzyme dissociates at guanidinium chloride concentration of less than 0.4 M, at which the enzymatic activity loss showes close correlation with the subunit dissociation. Further increase in guanidinium chloride induces a reversible biphasic unfolding of the enzyme.…”

“…porcine transmissible gastroenteritis virus Mpro severe acute respiratory syndrome coronavirus 3C-like protease <2> [41,42] severe acute respiratory syndrome coronavirus main protease <2> [21] severe acute respiratory syndrome coronavirus main proteinase <2> [33] CAS registry number 218925-73-6 37353- 2 Source Organism <1> alphacoronavirus [19] <2> SARS coronavirus [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,…”