A unified approach toward the rational design of selective low nanomolar human neutrophil elastase inhibitors
2015
Areias, L. R. P. | Ruivo, E. F. P. | Gonçalves, L. M. | Duarte, M. T. | André, V. | Moreira, R. | Lucas, S. D. | Guedes, R. C.
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.
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