Exploring the conformational binding mechanism of fibrinogen induced by interactions with penicillin β-lactam antibiotic drugs

Abstract

Herein, we present an integrated computational and experimental study to tackle the interactions between recognized β-lactam antibiotics (cloxacillin and dicloxacillin) with the fibrinogen blood plasma protein. For this purpose, molecular docking simulation with elastic network based on collective low-frequency normal modes and perturbation response scanning maps were proposed to evaluate the conformational binding mechanism of fibrinogen under the unbound and bound states with the cited β-lactam antibiotics. Aiming to theoretically explore the hidden biochemical mechanisms and structural attributes leading failures in therapy success with β-lactam antibiotics. The computational results pointing that despite these conformational differences, both antibiotics exhibit very similar affinity-based free energies of binding as FEB (cloxacillin/E-region) = − 8.7 kcal/mol and FEB (dicloxacillin/E-region) = −7.7 kcal/mol. We theoretically suggest that the semi-synthetic incorporation of an additional halogen CL-atom in the dicloxacillin, respect to cloxacillin molecule, and its relative docking-pose orientation in the fibrinogen E-region could significantly reduce the appearance of potential fibrinolytic off-target effects usually associated to parenterally administered β-lactam antibiotics. Besides, the performed interactions diagrams revealed that the most relevant antibiotic binding interactions with the fibrinogen E-region (pocket 1) are mainly based on hydrophobic (C···C)-backbone-side-chain non-covalent interactions, acceptor/donor interactions with critical regulatory E-region residues SER50:Q > SER50:N associated to allosteric modulation based long-distance-based perturbations (dicloxacillin > > cloxacillin) in the E-region (Q-chain > N-chain) with remarkable conformational rigidification by decreasing the intrinsic collectivity, and leading different pattern of perturbations as allosteric signal propagation in the intrinsic conformational dynamics under bound state from both β-lactam antibiotics. An experimental validation was carried out by using calorimetric (ITC and DSC) and spectroscopic (Raman and fluorescence) methods. These methods corroborated the computational results, adding quantitative information to explain the binding process. Finally, the obtained results open new perspectives for the “de novo rational drug-design” of new derivatives of β-lactam antibiotics with high pharmacodynamic selectivity/specificity to avoid side-effects toward to achieve optimal benefit/risk rates beyond the antibiotic drug resistance phenomena, favoring the implementation of rigorous criteria for a more personalized antibiotic therapy.