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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Niu C,Yin J,Zhang J,Vederas JC,James MNdoi
10.1016/j.bmc.2007.09.034subject
Has Abstractpub_date
2008-01-01 00:00:00pages
293-302issue
1eissn
0968-0896issn
1464-3391pii
S0968-0896(07)00820-6journal_volume
16pub_type
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