RT Journal Article
T1 Mapping the underlying mechanisms of fibrinogen benzothiazole drug interactions using computational and experimental approaches
A1 González Durruthy, Michael
A1 Scanavachi, Gustavo
A1 Rial Silva, Ramón
A1 Liu, Zhen
A1 Cordeiro, M. Natália D. S.
A1 Itri, Rosangela
A1 Ruso Beiras, Juan Manuel
K1 Fibrinogen
K1 BTS
K1 Molecular docking
K1 2D-FFT signals
K1 Fractal analysis
AB 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-mechanism of BTS-interaction mainly 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, we theoretically suggest that the BTS-binding modes 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.
PB Elsevier
YR 2020
FD 2020-07-06
LK https://hdl.handle.net/10347/43933
UL https://hdl.handle.net/10347/43933
LA eng
NO International Journal of Biological Macromolecules Volume 163, 15 November 2020, Pages 730-744
NO The authors acknowledge Ministerio de Ciencia e Innovación (PID2019-111327GB-100) and Xunta de Galicia (ED41E2018/08), G. Scanavachi thanks to CAPES PhD fellowship. R. Itri is recipient from National Council for Scientific and Technological Development (CNPq, Brazil) research fellowship. The work of M. G.-Durruthy and M. N. D. S. Cordeiro was supported by UIDB/50006/2020 with funding from FCT/MCTES through national funds. The authors would also like to thank to the LNLS/CNPEM (Campinas, Brazil) for the use of SAXS beamline.
DS Minerva
RD 24 abr 2026