The role of N-terminal heterocycles in hydrogen bonding to α-chymotrypsin
| dc.contributor.author | Schumann, N.C. | |
| dc.contributor.author | Bruning, J. | |
| dc.contributor.author | Marshall, A.C. | |
| dc.contributor.author | Abell, A.D. | |
| dc.date.issued | 2019 | |
| dc.description.abstract | A 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. | |
| dc.description.statementofresponsibility | Nicholas C.Schumann, John Bruning, Andrew C.Marshall, Andrew D.Abell | |
| dc.identifier.citation | Bioorganic and Medicinal Chemistry Letters, 2019; 29(3):396-399 | |
| dc.identifier.doi | 10.1016/j.bmcl.2018.12.032 | |
| dc.identifier.issn | 0960-894X | |
| dc.identifier.issn | 1464-3405 | |
| dc.identifier.orcid | Schumann, N.C. [0000-0002-6165-9066] | |
| dc.identifier.orcid | Bruning, J. [0000-0002-6919-1824] | |
| dc.identifier.orcid | Marshall, A.C. [0000-0002-9770-4594] | |
| dc.identifier.orcid | Abell, A.D. [0000-0002-0604-2629] | |
| dc.identifier.uri | http://hdl.handle.net/2440/118413 | |
| dc.language.iso | en | |
| dc.publisher | Elsevier | |
| dc.relation.grant | http://purl.org/au-research/grants/arc/CE140100003 | |
| dc.rights | © 2018 Elsevier Ltd. All rights reserved. | |
| dc.source.uri | https://doi.org/10.1016/j.bmcl.2018.12.032 | |
| dc.subject | Chymotrypsin | |
| dc.subject | Heterocycles | |
| dc.subject | Peptidic aldehydes | |
| dc.subject | Peptidomimetic | |
| dc.subject | Protease inhibitors | |
| dc.subject | β-Strand | |
| dc.title | The role of N-terminal heterocycles in hydrogen bonding to α-chymotrypsin | |
| dc.title.alternative | The role of N-terminal heterocycles in hydrogen bonding to alpha-chymotrypsin | |
| dc.type | Journal article | |
| pubs.publication-status | Published |