Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L
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Metadatos
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INVESTIGACIONMetadatos
Título
Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin LAutoría
Fecha de publicación
2023-10-03Editor
American Chemical SocietyISSN
2155-5435Cita bibliográfica
Fernández-de-la-Pradilla, A.; Royo, S.; Schirmeister, T.; Barthels, F.; Świderek, K.; González, F. V.; Moliner, V. Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L. ACS Catal. 2023, 13 (20), 13354-13368, DOI: 10.1021/acscatal.3c02748Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
https://pubs.acs.org/doi/full/10.1021/acscatal.3c02748Versión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
Cathepsin L (CatL) is a lysosomal cysteine protease whose activity has been related to several human pathologies. However, although preclinical trials using CatL inhibitors were promising, clinical trials have been ... [+]
Cathepsin L (CatL) is a lysosomal cysteine protease whose activity has been related to several human pathologies. However, although preclinical trials using CatL inhibitors were promising, clinical trials have been unsuccessful up to now. We are presenting a study of two designed dipeptidyl keto Michael acceptor potential inhibitors of CatL with either a keto vinyl ester or a keto vinyl sulfone (KVS) warhead. The compounds were synthesized and experimentally assayed in vitro, and their inhibition molecular mechanism was explored based on molecular dynamics simulations at the density functional theory/molecular mechanics level. The results confirm that both compounds inhibit CatL in the nanomolar range and show a time-dependent inhibition. Interestingly, despite both presenting almost equivalent equilibrium constants for the reversible formation of the noncovalent enzyme/inhibitor complex, differences are observed in the chemical step corresponding to the enzyme–inhibitor covalent bond formation, results that are mirrored by the computer simulations. Theoretically determined kinetic and thermodynamic results, which are in very good agreement with the experiments, afford a detailed explanation of the relevance of the different structural features of both compounds having a significant impact on enzyme inhibition. The unprecedented binding interactions of both inhibitors in the P1′ site of CatL represent valuable information for the design of inhibitors. In particular, the peptidyl KVS can be used as a starting lead compound in the development of drugs with medical applications for the treatment of cancerous pathologies since sulfone warheads have previously shown promising cell stability compared to other functions such as carboxylic esters. Future improvements can be guided by the atomistic description of the enzyme–inhibitor interactions established along the inhibition reaction derived from computer simulations. [-]
Publicado en
ACS catalysis, 2023, vol. 13, no 20Entidad financiadora
Ministerio de Ciencia e Innovación | Ministerio de Ciencia, Innovación y Universidades | Generalitat Valenciana | Universitat Jaume I | European Cooperation in Science and Technology (COST)
Identificador de la entidad financiadora
http://dx.doi.org/10.13039/501100011033
Código del proyecto o subvención
MCIN/PEICTI2021-2023/PGC2021-23332OB-C21 | MICIU/ICTI2017-2020/PID2019-107098RJ-I00 | CIPROM/2021/079 | UJI-B2020-03 | UJI-2021-71 | FPU AP-2020-03516 | RYC2020-030596-I | CA21101 | EQC2019-006018-P
Título del proyecto o subvención
Estudios computacionales del mecanismo y la inhibición de la proteólisis enzimática como enfoque complementario del mundo del descubrimiento moderno de fármacos
Derechos de acceso
info:eu-repo/semantics/openAccess
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