Molecular Modeling Technology Studies Of Novel Pyrazoylethylbenzamide Derivatives As Selective Orexin Receptor 1 Antagonists

Orexin neuropeptide signal is the core promoter of arousal,and orexin signaling is activated by orexin receptor 1(OX1R),which makes OX1R an attractive target for the treatment of insomnia.In this study,OX1R quantitative structure-activity relationship(QSAR)models(CoMFA:q2=0.788,r2=0.988;CoMSIA:q2=0.783,r2=0.953)were constructed based on the pIC50 values of 36 pyrazoylethylbenzamide derivatives.Results indicated that the models have good reliability and predictability.Furthermore,3D-QSAR contour maps reveal that the bioactivity of antagonists is most affected by hydrogen bond receptors.Molecular docking showed significant hydrogen bonds between key residues(ASN318 and SER103)and OX1R pocket were determined.Seven new more selective OX1R antagonists(DS01-DS07)were designed based on the contour maps and molecular docking results.The results of ADME prediction illustrated that the designed compounds had potential druggability and that the selectivity index value was higher than that of template molecule 33(SI=265).The molecular dynamics simulation results of compound 33 and DS01 indicated that their stability can be attributed to the hydrogen bonds between the nitrogen atom in the R1 region,the fluorine atom in the R4 region and the protein pockets.We constructed the orexin receptor 2(OX2R)QSAR models(CoMFA:q2=0.852,r2=0.979;CoMSIA:q2=0.823,r2=0.965)and compared them with models 1.Four potential new skeletal antagonists(Z1-Z4)were screened from the ZINC 12 database containing 1,020,679 compounds based on the pharmacophore model.The molecular docking indicated that the screened compounds formed additional hydrogen bond interaction with residues GLN176 and ARG322 of OX1R.The present study could offer theoretical guidance for future structural optimization,design,and synthesis of more selective OX1R antagonists.Designed and screened compounds might also be as candidate compounds for related research groups.