Design and interaction mechanism of ligand targeted with folate receptor α and β

Abstract

Four compounds 1 to 4 (folic acid, methotrexate and 2 dyes) were used to interact with folate receptor (FR)α and FRβ. The interaction structures and binding energies of the bound complexes were investigated. In order to analyze the differences between FRα and FRβ complexes, the details of the weak intermolecular interactions were analyzed, and the frontier orbital properties of the FR complexes were studied by a dispersion complemented density functional tight-binding method.By comparing the different interaction properties of the 4 compounds with FRα and FRβ, the basic strategies for design of novel compound targeted with FR subtype were suggested. Further, a novel compound with high selectively with FRα based on compound 3 was designed to illustrate our conclusion. These data should be helpful for the design of novel molecules with extreme discerningly with FRα and FRβ. For example, Chen et al [22] reported the crystal structure of human FRα bound to folic acid (FA) and indicated that FA is oriented with its basic pteroate moiety docked deep inside of the negatively charged pocket and the 2 carboxyl groups are solvent exposed and not involved in binding to FR. This research provided a template for the design of more specific drugs targeted with the FR system. Tang et al [23] combined magnetic-guided iron oxide nanoparticles with FA ligands and optimized the FA ligand density of the drug delivery system. Dong et al [24] adopted solid phase peptide synthesis to synthesize 2 isomeric copolymers, α-and γ-Fol-PEG-DSPE-DOX, and concluded that the micelles had greater antitumor effect and lower toxicity than the free DOX and MPEG-DSPE micelles. Qiao et al [25] immobilized the FA and amino-rhodamine B onto the PVDMA polymer to form a nano conjugates, RhB-PVDMA-FA, and indicated that the fluorescent nano conjugates have good biocompatibility and intracellular dispersibility and this method would be a promising candidate for optical imaging-based FR expression study. Tumor and inflammation express FRα and FRβ, respectively, but they can be targeted by folate conjugates simultaneously. Therefore, the research about the properties of folate derivative targeted with FRα and FRβ is significant. The molecular simulations could reveal that the details that could not be observed by experiment have been widely used by the researchers. For example, Sahoo et al [26] built the 3D model of bovine FOLR1 by molecular dynamics simulation, analyzed the stability of bvFOLR1-folate complex at different temperatures by binding energy calculation, and

Molecular Dynamics for the Optimal Design of Functionalized Nanodevices to Target Folate Receptors on Tumor Cells

“…In this respect, several theoretical studies, based on docking calculations and molecular dynamics (MD) simulations, have contributed to providing useful information on the FRα/FA interactions at an atomic resolution level. For instance, Gu and collaborators − combined density functional theory (DFT), MD, molecular docking, and molecular mechanics/Poisson–Boltzmann surface area free energy calculations to perform a screening of several folate and antifolate derivatives and to determine how substitutional functional groups could enhance the ligand–receptor interaction. Moreover, Della-Longa and Arcovito set up metadynamics calculations and reported a free energy barrier for the FA escape from FRα of 18 kcal mol –1 .…”