Theoretical study of the interaction between bioactive ligands and TGF-² receptor type 1 (ALK-5) using methods of molecular modeling

Abstract

This project proposes the use of molecular modeling techniques to understand the main factors related to electronic structure of TGF-² receptor type 1 (ALK-5) and a set of bioactive inhibitors. This biological target is involved in the development of diseases like cancer, fibrosis and pancreatic diseases. For the analysis of ligand-receptor interaction are realized computational methodologies of fundamental importance in the study of atoms and molecules are used. For this, the following computational methods are used: (I) molecular docking used to insert the ligands at the active site of ALK-5 and also to generate possible bioactive conformations of the compounds; (II) molecular dynamics method, used for evaluating the atomic position of the system as a function of time; (III) hybrid methods (QM / MM), using the ONIOM package in the Gaussian 09 program, used to obtain molecular properties relevant to study the electronic structure of the biological target and the selected inhibitors; (IV) NBO analysis, allowing describe the electron density in terms of hybridization and covalent effects in polyatomic wave functions between the inhibitors and main amino acids of the active site of ALK-5 receptor; (V) study of the quantum theory of atoms in molecules of Bader (QTAIM) to determine the positions of the critical points of the gradient of the electron density of the inhibitors and the main waste of the active site and subsequently calculate the electron densities of these critical points using QTAIM theory. Thus, it is considered that the use of molecular modeling methodologies will be of fundamental importance for the study of the interaction between target ALK-5 and their inhibitors. (AU)