A unified approach toward the rational design of selective low nanomolar human neutrophil elastase inhibitorsElectronic supplementary information (ESI) available: Computational methods description, molecular data sets for pharmacophoric generation and validation, docking poses for compound 1, chemical synthesis, NMR spectra, X-ray crystallographic data for compounds 1 and 3 and detailed description on biochemical assays. CCDC 1022848 and 1022849. For ESI and crystallographic data in CIF or other

• Main Authors: Areias, L. R. P, Ruivo, E. F. P, Gonçalves, L. M, Duarte, M. T, André, V, Moreira, R, Lucas, S. D, Guedes, R. C
• Format: Journal Article
• Language: English
• Published: 11.06.2015
• ISSN: 2046-2069
• DOI: 10.1039/c5ra07783d

A computer-aided campaign boosted the discovery of potent human neutrophil elastase (HNE) inhibitors. A pharmacophoric model was developed, validated and applied to filter an oxo-beta-lactam library previously generated by de novo design. This campaign led us to compound 1 which showed an inhibitory activity of 6.9 nM against HNE, more active than the only commercially available HNE inhibitor for therapeutic usage. Computer-aided methodologies proved again to be powerful tools to increase the rate of success for HNE inhibitor discovery either for therapeutic or activity-based probing development. A computer-aided campaign boosted the discovery of potent human neutrophil elastase (HNE) inhibitors.