Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors
- Vera M. S. IscaVera M. S. IscaCenter for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, PortugalInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, PortugalMore by Vera M. S. Isca
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- Ricardo J. Ferreira*Ricardo J. Ferreira*Email: [email protected]Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, PortugalScience for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, 75124 Uppsala, SwedenMore by Ricardo J. Ferreira
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- Catarina GarciaCatarina GarciaCenter for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, PortugalDepartment of Biomedical Sciences, Faculty of Pharmacy, University of Alcalá, Campus Universitario, 28871 Alcalá de Henares, SpainMore by Catarina Garcia
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- Carlos M. MonteiroCarlos M. MonteiroInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, PortugalMore by Carlos M. Monteiro
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- Jelena DinicJelena DinicInstitute for Biological Research “Siniša Stanković“, National Institute of Republic of Serbia University of Belgrade, Despota Stefana 142, 11060 Belgrade, SerbiaMore by Jelena Dinic
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- Suvi HolmstedtSuvi HolmstedtFaculty of Engineering and Natural Sciences, Tampere University, Korkeakoulunkatu 8, 33101 Tampere, FinlandMore by Suvi Holmstedt
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- Vânia AndréVânia AndréCentro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, PortugalMore by Vânia André
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- Milica PesicMilica PesicInstitute for Biological Research “Siniša Stanković“, National Institute of Republic of Serbia University of Belgrade, Despota Stefana 142, 11060 Belgrade, SerbiaMore by Milica Pesic
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- Daniel J. V. A. dos SantosDaniel J. V. A. dos SantosInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, PortugalLAQV@REQUIMTE/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, PortugalMore by Daniel J. V. A. dos Santos
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- Nuno R. CandeiasNuno R. CandeiasFaculty of Engineering and Natural Sciences, Tampere University, Korkeakoulunkatu 8, 33101 Tampere, FinlandLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalMore by Nuno R. Candeias
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- Carlos A. M. AfonsoCarlos A. M. AfonsoInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, PortugalMore by Carlos A. M. Afonso
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- Patrícia Rijo*Patrícia Rijo*Email: [email protected]Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, PortugalInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, PortugalMore by Patrícia Rijo
Abstract
The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diterpenes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemisynthesis from natural compounds 1 and 2 to achieve a small library of products with enhanced anti-P-glycoprotein activity. Nonetheless, some derivatives tend to be unstable. Therefore, to reason such lack of stability, the electron density based local reactivity descriptors condensed Fukui functions and dual descriptor were calculated for several derivatives of DHR. Additionally, molecular docking and molecular dynamics studies were performed on several other derivatives to clarify the molecular mechanisms by which they may exert their inhibitory effect in P-gp activity. The analysis on local reactivity descriptors was important to understand possible degradation pathways and to guide further synthetic approaches toward new royleanone derivatives. A molecular docking study suggested that the presence of aromatic moieties increases the binding affinity of royleanone derivatives toward P-gp. It further suggests that one royleanone benzoylated derivative may act as a noncompetitive efflux modulator when bound to the M-site. The future generation of novel royleanone derivatives will involve (i) a selective modification of position C-12 with chemical moieties smaller than unsubstituted benzoyl rings and (ii) the modification of the substitution pattern of the benzoyloxy moiety at position C-6.
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