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Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L
dc.contributor.author | Fernández de la Pradilla Ibáñez, Adrián | |
dc.contributor.author | Royo, Santiago | |
dc.contributor.author | Schirmeister, Tanja | |
dc.contributor.author | Barthels, Fabian | |
dc.contributor.author | Świderek, Katarzyna | |
dc.contributor.author | González, Florenci | |
dc.contributor.author | Moliner, Vicent | |
dc.date.accessioned | 2023-12-22T07:58:34Z | |
dc.date.available | 2023-12-22T07:58:34Z | |
dc.date.issued | 2023-10-03 | |
dc.identifier.citation | 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.3c02748 | ca_CA |
dc.identifier.issn | 2155-5435 | |
dc.identifier.uri | http://hdl.handle.net/10234/205266 | |
dc.description.abstract | 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. | ca_CA |
dc.description.sponsorShip | Funding for open access charge: CRUE-Universitat Jaume I | |
dc.format.extent | 15 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | American Chemical Society | ca_CA |
dc.relation | Estudios computacionales del mecanismo y la inhibición de la proteólisis enzimática como enfoque complementario del mundo del descubrimiento moderno de fármacos | ca_CA |
dc.relation.isPartOf | ACS catalysis, 2023, vol. 13, no 20 | ca_CA |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | ca_CA |
dc.subject | cathepsin L | ca_CA |
dc.subject | inhibitor | ca_CA |
dc.subject | QM/MM | ca_CA |
dc.subject | MD | ca_CA |
dc.subject | Michael acceptor | ca_CA |
dc.title | Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1021/acscatal.3c02748 | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | https://pubs.acs.org/doi/full/10.1021/acscatal.3c02748 | ca_CA |
dc.description.sponsorship | This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (grant PGC2021-23332OB-C21 and PID2019-107098RJ-I00), the Generalitat Valenciana (PROMETEO, with ref CIPROM/2021/079), and Universitat Jaume I (UJI-B2020-03 and UJI-2021-71). A.F.P thanks MINECO for the doctoral FPU grant (FPU AP-2020-03516). K.Ś. thanks the Ministerio de Ciencia e Innovación and Fondo Social Europeo for a Ramon y Cajal contract (ref. RYC2020-030596-I) and a European Cooperation in Science & Technology COST Action (ref CA21101). The authors thankfully acknowledge the computational resources funded by the Spanish Ministry of Science─European Regional Development Fund (REF: EQC2019-006018-P) installed at Universitat Jaume I, the Servei d’Informàtica and Serveis Centrals d’Instrumentació Científica of Universitat Jaume I. | |
dc.type.version | info:eu-repo/semantics/publishedVersion | ca_CA |
project.funder.identifier | http://dx.doi.org/10.13039/501100011033 | ca_CA |
project.funder.name | Ministerio de Ciencia e Innovación | ca_CA |
project.funder.name | Ministerio de Ciencia, Innovación y Universidades | ca_CA |
project.funder.name | Generalitat Valenciana | ca_CA |
project.funder.name | Universitat Jaume I | ca_CA |
project.funder.name | European Cooperation in Science and Technology (COST) | ca_CA |
oaire.awardNumber | MCIN/PEICTI2021-2023/PGC2021-23332OB-C21 | ca_CA |
oaire.awardNumber | MICIU/ICTI2017-2020/PID2019-107098RJ-I00 | ca_CA |
oaire.awardNumber | CIPROM/2021/079 | ca_CA |
oaire.awardNumber | UJI-B2020-03 | ca_CA |
oaire.awardNumber | UJI-2021-71 | ca_CA |
oaire.awardNumber | FPU AP-2020-03516 | ca_CA |
oaire.awardNumber | RYC2020-030596-I | ca_CA |
oaire.awardNumber | CA21101 | ca_CA |
oaire.awardNumber | EQC2019-006018-P | ca_CA |
dc.subject.ods | 3. Salud y bienestar | ca_CA |
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