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Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L
dc.contributor.author | Arafet Cruz, Kemel | |
dc.contributor.author | Royo, Santiago | |
dc.contributor.author | Schirmeister, Tanja | |
dc.contributor.author | Barthels, Fabian | |
dc.contributor.author | González, Florenci | |
dc.contributor.author | Moliner, Vicent | |
dc.date.accessioned | 2023-06-09T08:04:01Z | |
dc.date.available | 2023-06-09T08:04:01Z | |
dc.date.issued | 2023-05-05 | |
dc.identifier.citation | Arafet, K.; Royo, S.; Schirmeister, T.; Barthels, F.; González, F. V.; Moliner, V.Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L. ACS Catal. 2023, 13, 9, 6289–6300. DOI: https://doi.org/10.1021/acscatal.3c01035 | ca_CA |
dc.identifier.issn | 2155-5435 | |
dc.identifier.uri | http://hdl.handle.net/10234/202767 | |
dc.description.abstract | Cysteine proteases (CPs) are an important class of enzymes, many of which are responsible for several human diseases. For instance, cruzain of protozoan parasite Trypanosoma cruzi is responsible for the Chagas disease, while the role of human cathepsin L is associated with some cancers or is a potential target for the treatment of COVID-19. However, despite paramount work carried out during the past years, the compounds that have been proposed so far show limited inhibitory action against these enzymes. We present a study of proposed covalent inhibitors of these two CPs, cruzain and cathepsin L, based on the design, synthesis, kinetic measurements, and QM/MM computational simulations on dipeptidyl nitroalkene compounds. The experimentally determined inhibition data, together with the analysis and the predicted inhibition constants derived from the free energy landscape of the full inhibition process, allowed describing the impact of the recognition part of these compounds and, in particular, the modifications on the P2 site. The designed compounds and, in particular, the one with a bulky group (Trp) at the P2 site show promising in vitro inhibition activities against cruzain and cathepsin L for use as a starting lead compound in the development of drugs with medical applications for the treatment of human diseases and future designs. | ca_CA |
dc.description.sponsorShip | Funding for open access charge: CRUE-Universitat Jaume I | |
dc.format.extent | 12 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.isPartOf | ACS catalysis, 2023, vol. 13, no 9 | ca_CA |
dc.relation.uri | https://figshare.com/collections/Impact_of_the_Recognition_Part_of_Dipeptidyl_Nitroalkene_Compounds_on_the_Inhibition_Mechanism_of_Cysteine_Proteases_Cruzain_and_Cathepsin_L/6613814 | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | ca_CA |
dc.subject | cysteine proteases | ca_CA |
dc.subject | cathepsin L | ca_CA |
dc.subject | cruzain | ca_CA |
dc.subject | dipeptidyl nitroalkenes | ca_CA |
dc.subject | inhibitory activities | ca_CA |
dc.subject | QM/MM | ca_CA |
dc.subject | free energy surfaces | ca_CA |
dc.subject | in vitro activities | ca_CA |
dc.title | Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1021/acscatal.3c01035 | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | https://pubs.acs.org/doi/full/10.1021/acscatal.3c01035 | ca_CA |
dc.description.sponsorship | This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant PGC2021-23332OB-C21), Generalitat Valenciana and the European Regional Funds (Grant PROMETEO CIPROM/2021/079, IDIFEDER/2021/027), and Universitat Jaume I (UJI-B2020-03 and UJI-2021-71). K.A. thanks Generalitat Valenciana (APOSTD/2020/015) for a postdoctoral contract. The authors thankfully acknowledge the local computational resources of 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.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 | Generalitat Valenciana | ca_CA |
oaire.awardNumber | PGC2021-23332OB-C21 | ca_CA |
oaire.awardNumber | Grant PROMETEO CIPROM/2021/079 | ca_CA |
oaire.awardNumber | IDIFEDER/2021/027 | ca_CA |
oaire.awardNumber | UJI-B2020-03 | ca_CA |
oaire.awardNumber | UJI-2021-71 | ca_CA |
oaire.awardNumber | APOSTD/2020/015 | ca_CA |
dc.subject.ods | 3. Salud y bienestar |
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