Depression is a serious and common disorder worldwide, and its recurrence is closely linked to the damage done to the lives of those affected. Its main features, such as depressed mood, anhedonia, irritability, difficulty concentrating, fatigue, increased or decreased appetite, insomnia or hypersomnia, and cognitive and motor losses, justify its severity. Current treatments cause many side effects and it takes a long time for the therapeutic effect to take hold, highlighting the need for the development of new drugs. In the last two decades, several studies have shown that the nociceptin/orphanin FQ peptide receptor (NOPR), a member of the opioid receptor subfamily of G protein-coupled receptors (GPCRs), can be a valuable therapeutic target in the field of pharmacological therapy, and its antagonism has emerged as a promising strategy due to the antidepressant effect reported in preclinical and clinical studies. Drug discovery efforts targeting NOPR have yielded a variety of agonists and antagonists in the form of small molecules, such as SB-612111 (SB) and compound 35 (C-35), two NOPR antagonists with the highest affinity. In this sense, the present work aims to evaluate, by computer simulation techniques using Functional Density Theory (DFT) and Molecular Fractionation Method with Conjugate Caps (MFCC), the energetic features involved in the interaction between the NOP receptor and the ligands SB and C-35, which are antagonists. By obtaining the crystalline structures in the PDB, it was possible to analyse the energetic contributions in each complex formed by these binders and the receptor in question. A total of 102 (101) amino acid fragments were observed for SB (C-35), with most of the energetically relevant residues being part of the hydrophobic binding pocket and the fragments with the most attractive energy being up to 3 Å away in both complexes: NOP/SB (ASP130 > GLN107 > TYR309 > TYR131); NOP/C-35 (ASP130 > GLN107 > ASP110 > ILE127 > TYR131 > GLN280 > TYR309). The results presented and discussed here are of considerable importance given the intense research and investment in the development of more effective antidepressants in recent decades. Therefore, the analyses described here may help to further develop the pharmacological scenario for antidepressants targeting the NOP receptor.