Identification of potential agonist-like molecules for α2-adrenergic receptor by multi-layer virtual screening to...

Sinusitis is one of the most common respiratory inflammatory conditions and a significant health issue that affects millions of people worldwide with a global prevalence of 10-15%. The side effects of available drug regimens of sinus infection demand the urgent development of new drug candidates to combat sinusitis. With the aim of identifying new drug-like candidates to control sinus, we have conducted multifold comprehensive screening of drug-like molecules targeting α2-adrenergic receptor (α2-AR), which serve as the primary drug target in sinusitis. By structure-based virtual screening of in-house compound's database, ten molecules (CP1-CP10) with agonistic effects for α2-AR were selected, and their binding mechanism with critical residues of α2-AR and their physicochemical properties were studied. Moreover, the process of receptor activation by these compounds and the conformational changes in α2-AR caused by these molecules, were further explored by molecular dynamic simulation. The MM-PBSA estimated free energies of compounds are higher than that of reference agonist (ΔG_TOTAL = -39.0 kcal/mol). Among all, CP2-CP3, CP7-CP8 and CP6 have the highest binding free energies of -78.9 kcal/mol, -77.3 kcal/mol, -75.60 kcal/mol, -64.8 kcal/mol, and -61.6 kcal/mol, respectively. While CP4 (-55.0 kcal/mol), CP5 (-49.2 kcal/mol), CP9 (-54.8 ± 0.07 kcal/mol), CP10 (-56.7 ± 0.10 kcal/mol) and CP1 (-46.0 ± 0.08 kcal/mol) also exhibited significant binding free energies. These energetically favorable binding energies indicate strong binding affinity of our compounds for α2-AR as compared to known partial agonist. Therefore, these molecules can serve as excellent drug-like candidates for sinusitis.