Back to Search Start Over

Protein binding of lapatinib and its N- and O-dealkylated metabolites interrogated by fluorescence, ultrafast spectroscopy and molecular dynamics simulations

Authors :
Universitat Politècnica de València. Departamento de Química - Departament de Química
Universitat Politècnica de València. Instituto Universitario Mixto de Tecnología Química - Institut Universitari Mixt de Tecnologia Química
Xunta de Galicia
Generalitat Valenciana
Instituto de Salud Carlos III
Agencia Estatal de Investigación
European Regional Development Fund
Ministerio de Economía y Competitividad
Andreu Ros, María Inmaculada
Lence, Emilio
González-Bello, Concepción
Mayorga, Cristobalina
Cuquerella Alabort, Maria Consuelo
Vayá Pérez, Ignacio
Miranda Alonso, Miguel Ángel
Universitat Politècnica de València. Departamento de Química - Departament de Química
Universitat Politècnica de València. Instituto Universitario Mixto de Tecnología Química - Institut Universitari Mixt de Tecnologia Química
Xunta de Galicia
Generalitat Valenciana
Instituto de Salud Carlos III
Agencia Estatal de Investigación
European Regional Development Fund
Ministerio de Economía y Competitividad
Andreu Ros, María Inmaculada
Lence, Emilio
González-Bello, Concepción
Mayorga, Cristobalina
Cuquerella Alabort, Maria Consuelo
Vayá Pérez, Ignacio
Miranda Alonso, Miguel Ángel
Publication Year :
2020

Abstract

[EN] Lapatinib (LAP) is an anticancer drug generally used to treat breast and lung cancer. It exhibits hypersensitivity reactions in addition to dermatological adverse effects and photosensitivity. Moreover, LAP binds to serum proteins and is readily biotransformed in humans, giving rise to several metabolites, such as N- and O-dealkylated products (N-LAP and O-LAP, respectively). In this context, the aim of the present work is to obtain key information on drug@protein complexation, the first step involved in a number of hypersensitivity reactions, by a combination of fluorescence, femtosecond transient absorption spectroscopy and molecular dynamics (MD) simulations. Following this approach, the behavior of LAP and its metabolites has been investigated in the presence of serum proteins, such as albumins and alpha(1)-acid glycoproteins (SAs and AGs, respectively) from human and bovine origin. Fluorescence results pointed to a higher affinity of LAP and its metabolites to human proteins; the highest one was found for LAP@HSA. This is associated to the coplanar orientation adopted by the furan and quinazoline rings of LAP, which favors emission from long-lived (up to the ns time-scale) locally-excited (LE) states, disfavoring population of intramolecular charge transfer (ICT) states. Moreover, the highly constrained environment provided by subdomain IB of HSA resulted in a frozen conformation of the ligand, contributing to fluorescence enhancement. Computational studies were clearly in line with the experimental observations, providing valuable insight into the nature of the binding sites and the conformational arrangement of the ligands inside the protein cavities. Besides, a good correlation was found between the calculated binding energies for each ligand@protein complex and the relative affinities observed in competition experiments.

Details

Database :
OAIster
Notes :
TEXT, English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1258894340
Document Type :
Electronic Resource