Computational studies of pyrimidine derivatives as inhibitors of human 1 receptor using 3D-QSAR analysis, molecular docking, ADMET properties and DFT investigation

Neuropathic pain syndrome has a profoundly negative and agonizing impact on the lives of the individuals it afflicts. In order to find an effective treatment for this condition, extensive and thorough scientific studies have demonstrated that the sigma 1 receptor serves as an exceptional target for therapeutic compounds. The 3D-QSAR studies were constructed using the technique of comparative molecular similarity indice analysis (CoMSIA). The outcomes of these studies demonstrated the reliability of CoMSIA model (with R2 train value of 0.96 and Q(2 )value of 0.54) in accurately predicting the activity of various compounds. By assimilating the valuable insights gathered from the field contributors of the 3D-QSAR models and conducting molecular docking studies on the highly potent compound C48, a total of sixteen new compounds were successfully designed to exhibit enhanced efficacy against neuropathic pain. In addition to the comprehensive 3D-QSAR analysis, the newly synthesized compounds were subjected to an absorption, distribution, metabolism, excretion, and toxicity evaluation. This evaluation aimed to assess the pharmacokinetic and toxicological properties of the compounds, providing valuable insight for future in vitro investigations. Calculations DFT of the new compounds mol2, mol3, and mol4, including the analysis of their molecular properties, geometric optimization, frontier molecular orbital (FMOs), density states (DOS), and energy evaluation, In order to compare these compounds with the reference ligand 61 w, their respective properties were thoroughly investigated. The most stable orientations for the compounds Mol2, Mol4, and Mol3 were determined to be the ones that yielded the highest stability and efficiency. The significant advancements made in this study, should serve as a strong motivation for future in vitro investigations on these compounds.