Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro

Abstract

The 3C-like main proteinase of the severe acute respiratory syndrome (SARS) coronavirus, SARS-CoV M(pro), is widely considered to be a major drug target for the development of anti-SARS treatment. Based on the chemical structure of a lead compound from a previous screening, we have designed and synthesized a number of non-peptidyl inhibitors, some of which have shown significantly improved inhibitory activity against SARS-CoV M(pro) with IC(50) values of approximately 60 nM. In the absence of SARS-CoV M(pro) crystal structures in complex with these synthetic inhibitors, molecular docking tools have been employed to study possible interactions between these inhibitors and SARS-CoV M(pro). The docking results suggest two major modes for the initial binding of these inhibitors to the active site of SARS-CoV M(pro). They also establish a structural basis for the 'core design' of these inhibitors by showing that the 3-chloropyridine functions common to all of the present inhibitors tend to cluster in the S1 specificity pocket. In addition, intrinsic flexibility in the S4 pocket allows for the accommodation of bulky groups such as benzene rings, suggesting that this structural plasticity can be further exploited for optimizing inhibitor-enzyme interactions that should promote a tighter binding mode. Most importantly, our results provide the structural basis for rational design of wide-spectrum antiviral drugs targeting the chymotrypsin-like cysteine proteinases from coronaviruses and picornaviruses.

Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors

“…The model suggests that the indole group of 10 shifts and positions itself where the leaving group was in the complex, more towards the S1 pocket. This positioning of inhibitor 10 in the complex is not surprising as a similar orientation has been proposed before by James’ group for similar esters 23,24. More importantly though is the obvious pi-pi stacking of the indolyl of 10 with the imidazole ring of HIS41, which is also seen in the benzotriazole group of the referenced crystal structure (2V6N) 20.…”

Recent Advances in Targeting Viral Proteases for the Discovery of Novel Antivirals

“…(11)), which inactivate SARSCoV M pro with submicromolar affinities, possibly in a covalent manner by nucleophilic attack of the Cys 145 sulphur onto the ester functionality [129].…”

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“…Those genes are translated into polyproteins that are processed by the main protease (M pro ) as well as a papain-like protease 2 (PL2) to form the viral polymerase and associated nonstructural proteins (Ziebuhr et al, 2007). The main protease of coronaviruses appears to be the most attractive target for antiviral compounds (Haagmans and Osterhaus, 2006;Niu et al, 2008;Xue et al, 2008;Yang et al, 2005Yang et al, , 2006. Inhibitors of M pro include a Michael acceptor inhibitor (designated N3), chloromethyl ketones, epoxides, and AG7088 an inhibitor shown to be effective against the rhinovirus M pro homolog (Anand et al, 2003;Niu et al, 2008;Xue et al, 2008).…”

“…The main protease of coronaviruses appears to be the most attractive target for antiviral compounds (Haagmans and Osterhaus, 2006;Niu et al, 2008;Xue et al, 2008;Yang et al, 2005Yang et al, , 2006. Inhibitors of M pro include a Michael acceptor inhibitor (designated N3), chloromethyl ketones, epoxides, and AG7088 an inhibitor shown to be effective against the rhinovirus M pro homolog (Anand et al, 2003;Niu et al, 2008;Xue et al, 2008). Other antiviral compounds like hexamethylene amiloride (HMA) target ion channel conductance, and have been shown to have an antiviral effect against human coronavirus (HCoV)-229E and mouse hepatitis virus (MHV) coronavirus in vitro (Wilson et al, 2006).…”