Mapping the underlying mechanisms of fibrinogen benzothiazole drug interactions using computational and experimental approaches

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Gonzalez Durruthy, M (Author) Other; Scanavachi, G (Author) Other; Rial, R (Author) Other; Liu, Z (Author) Other; Natalia N D S Cordeiro (Author) FCUP; Itri, R (Author) Other; Ruso, JM (Author) Other

Journal

Title: International Journal of Biological Macromolecules

Vol. 163

Pages: 730-744

ISSN: 0141-8130

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 4 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00S-FS0

DOI: 10.1016/j.ijbiomac.2020.07.044

Abstract (EN): Three-dimensional conformational crystallographic binding-modes are of paramount importance to understand the docking mechanism of protein-ligand interactions and to identify potential "leading drugs" conformers towards rational drugs-design. Herein, we present an integrated computational-experimental study tackling the problem of multiple binding modes among the ligand 3-(2-Benzothiazolylthio)-propane sulfonic acid (BTS) and the fibrinogen receptor (E-region). Based on molecular docking simulations, we found that the free energy of binding values for nine of different BTS-docking complexes (i.e., BTS-pose_1-9) were very close. We have also identified a docking-mechanismof BTS-interactionmainly based on non-covalent hydrophobic interactions with H-bond contacts stabilizing the fibrinogen-BTS docking complexes. Interestingly, the different BTS-poses_1-9 were found to be able to block the fibrinogen binding site (E-region) by inducing local perturbations in effector and allosteric residues, reducing the degree of collectivity in its flexibility normal modes. As such, wetheoretically suggest that the BTS-bindingmodes can significantly affect the physiological condition of the unoccupied fibrinogen protein structure by bringing global and local perturbations in the frequency domain spectra. The proposed theoretical mechanisms, the interactions involved and the conformational changes suggested, were further corroborated by different experimental techniques such as isothermal titration calorimetry (ITC), zeta potential, UV-vis, fluorescence and small angle X-ray scattering (SAXS). The combined results shall open new avenues towards the application of complex supra-molecular information in rational drugs-design.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15