Predição in silico e dinâmica molecular de ligantes naturais do receptor de peptídeo formilado 1

Abstract

This study describes the design and in silico selection of novel candidate inhibitors for the formyl peptide receptor 1 (FPR1). Initially, a three-dimensional pharmacophore model was generated based on the reference ligand tBOC-MLF, mapping two hydrophobic centers, an aromatic region, a hydrogen-bond donor vector, and steric volume constraints. This model was employed in a pharmacophore-based virtual screening combined with molecular docking, using the NuBBE and Molport databases. The top five hits were subjected to pharmacokinetic (ADMET) prediction and molecular dynamics (MD) simulations to evaluate RMSD, RMSF, PCA, hydrogen bonding, and binding free energy via MM/PBSA. The virtual screening, followed by ADMET analysis and molecular docking, identified five compounds: NB975, NB540, NB538, MP001-519-139 and NB556. NB975 and MP001-915-139 stood out, exhibiting lower toxicity compared to tBOC-MLF. In dynamic simulations, NB975 mimicked the conformational behavior of the free receptor without causing significant structural perturbations. MP001-915-139 induced a rapid and stable conformational change in the receptor with a favorable, continuous energy profile (-28 kcal/mol). Meanwhile, NB540 illustrated the target's plasticity, converging toward an alternative and energetically stable conformational arrangement. The results highlight the chemodiverse potential of selected natural products and synthetic derivatives, providing scaffolds for the development of new drugs targeting the FPR1 receptor.