Schumann, N.C.Bruning, J.Marshall, A.C.Abell, A.D.2019-03-272019-03-272019Bioorganic and Medicinal Chemistry Letters, 2019; 29(3):396-3990960-894X1464-3405http://hdl.handle.net/2440/118413A series of dipeptide aldehydes containing different N-terminal heterocycles was prepared and assayed in vitro against α-chymotrypsin to ascertain the importance of the heterocycle in maintaining a β-strand geometry while also providing a hydrogen bond donor equivalent to the backbone amide nitrogen of the surrogate amino acid. The dipeptide containing a pyrrole constraint (10) was the most potent inhibitor, with >30-fold improved activity over dipeptides which lacked a nitrogen hydrogen bond donor (namely thiophene 11, furan 12 and pyridine 13). Molecular docking studies of 10 bound to α-chymotrypsin demonstrates a hydrogen bond between the pyrrole nitrogen donor and the backbone carbonyl of Gly216 located in the S3 pocket which is proposed to be critical for overall binding.en© 2018 Elsevier Ltd. All rights reserved.ChymotrypsinHeterocyclesPeptidic aldehydesPeptidomimeticProtease inhibitorsβ-StrandJournal article003010600710.1016/j.bmcl.2018.12.0320004564068000102-s2.0-85058630704453645Schumann, N.C. [0000-0002-6165-9066]Bruning, J. [0000-0002-6919-1824]Marshall, A.C. [0000-0002-9770-4594]Abell, A.D. [0000-0002-0604-2629]