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Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza ‐decaline scaffold
Author(s) -
Teruya Kenta,
Hattori Yasunao,
Shimamoto Yasuhiro,
Kobayashi Kazuya,
Sanjoh Akira,
Nakagawa Atsushi,
Yamashita Eiki,
Akaji Kenichi
Publication year - 2016
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22773
Subject(s) - chemistry , protease , ligand (biochemistry) , stereochemistry , protease inhibitor (pharmacology) , peptide , crystal structure , enzyme , crystallography , biochemistry , receptor , virus , virology , antiretroviral therapy , viral load , biology
Design of inhibitors against severe acute respiratory syndrome (SARS) chymotrypsin‐like protease (3CL pro ) is a potentially important approach to fight against SARS. We have developed several synthetic inhibitors by structure‐based drug design. In this report, we reveal two crystal structures of SARS 3CL pro complexed with two new inhibitors based on our previous work. These structures combined with six crystal structures complexed with a series of related ligands reported by us are collectively analyzed. To these eight complexes, the structural basis for inhibitor binding was analyzed by the COMBINE method, which is a chemometrical analysis optimized for the protein–ligand complex. The analysis revealed that the first two latent variables gave a cumulative contribution ratio of r 2 = 0.971. Interestingly, scores using the second latent variables for each complex were strongly correlated with root mean square deviations (RMSDs) of side‐chain heavy atoms of Met 49 from those of the intact crystal structure of SARS‐3CL pro (r = 0.77) enlarging the S 2 pocket. The substantial contribution of this side chain (∼10%) for the explanation of pIC 50 s was dependent on stereochemistry and the chemical structure of the ligand adapted to the S 2 pocket of the protease. Thus, starting from a substrate mimic inhibitor, a design for a central scaffold for a low molecular weight inhibitor was evaluated to develop a further potent inhibitor. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 391–403, 2016.