Prospecção virtual de potenciais antagonistas do receptor 2 do fator de liberação de corticotrofina

Abstract

Anxiety is an essential physiological response for the adaptation and survival of animals; however, when excessive and persistent, it may develop into anxiety disorders, conditions that are highly prevalent and associated with significant impacts on public health. In this context, the corticotropin-releasing factor (CRF) stands out. CRF is both a hormone involved in the hypothalamic–pituitary–adrenal (HHA) axis and a neuropeptide whose overexpression is directly associated with responses to adverse stimuli. Consequently, CRF is involved in the pathogenesis of anxiety, making it a potential pharmacological target, particularly through its receptors. Among them is the corticotropin-releasing factor receptor type 2 (CRF2R), a G protein–coupled receptor that remains poorly studied and for which conflicting results exist regarding its role in the biology of anxiety. Therefore, the present study aimed to identify potential antagonists of CRF2R through computational drug design approaches. Initially, using the receptor structure (PDB ID: 2JND), crystallized in complex with the antagonist astressin, a pharmacophore model was constructed based on the main interactions of the receptor–ligand complex. Subsequently, the following three small-molecule’s databases were selected and filtered using the FILTER and QUACPAC software tools: NuBBe, CNS-MPO, and Natural Products. The resulting compounds were then subjected to virtual screening followed by molecular docking using the MOE software. For the top-ranked molecule from each database, molecular dynamics (MD) simulations were performed using the GROMACS software, together with astressin and the receptor in its apo state. Finally, pharmacokinetic and toxicity predictions for the three selected ligands were carried out using the pkCSM platform. The quality of the interaction between each tested molecule and the target receptor was evaluated using the following metrics: RMSD, RMSF, number of hydrogen bonds, and binding energy analysis. The results indicate that, although the molecules showed some predicted toxicity, they also demonstrated potential to interact with the protein, particularly the compound MolPort-029-885-470. Therefore, further studies are required to better characterize these molecules and evaluate their pharmacological potential as CRF2R antagonists.