Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity
Martínez-Asensio, Miguel (Universitat Ramon Llull)
Sàrrias, Lluís (Universitat Ramon Llull)
Gorjón-de-Pablo, Gema (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Fernández-Serrano, Miranda (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Camaló-Vila, Judith (Universitat Ramon Llull)
Gibert, Albert (Universitat Ramon Llull)
Puig de la Bellacasa, Raimon (Universitat Ramon Llull)
Teixidó, Jordi (Universitat Ramon Llull)
Roué, Gaël (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Borrell, José I. (Universitat Ramon Llull)
Estrada-Tejedor, Roger (Universitat Ramon Llull)

Date:	2024
Abstract:	The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates.
Grants:	Agencia Estatal de Investigación PID2021-123039OB-C22 Agencia Estatal de Investigación PID2021-123039OB-C21
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	CXCR4 ; Virtual screening ; Molecular design ; DLBCL
Published in:	International journal of molecular sciences, Vol. 25 Núm. 17 (August 2024) , ISSN 1422-0067

DOI: 10.3390/ijms25179446
PMID: 39273392

14 p, 3.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles