Therapeutic Path to Double Knockout: Investigating the Selective Dual-Inhibitory Mechanisms of Adenosine Receptors A1 and A2 by a Novel Methoxy-Substituted Benzofuran Derivative in the Treatment of Parkinson's Disease.

摘要: The dual inhibition of adenosine receptors A1 (A1 AR) and A2 (A2A has been considered as an efficient strategy in the treatment Parkinson's disease (PD). This led to recent development a series methoxy-substituted benzofuran derivatives among which compound 3j exhibited dual-inhibitory potencies micromolar range. Therefore, this study, we seek resolve mechanisms by novel elicits its selective targeting against AR A2A AR. Unique binding both proteins, from our findings, is ring-ring interaction elicited A1Phe275 (→ A2Phe170) with ring compound. As observed, π-stacking contributes notably stability at active sites Besides, conserved site residues proteins such A1Ala170 A2Ala65), A1Ile173 A2Ile68), A1Val191 A2Val86), A1Leu192 A2Leu87), A1Ala195 A2Ala90), A1Met284 A2Met179), A1Tyr375 A2Tyr369), A1Ile378 A2Ile372), A1His382 A2His376) were commonly involved other substituents further complement 3j. reflects similar mechanism that aromatic (π) interactions. Consequentially, vdW energies contributed immensely compound, culminated high ΔGbinds homogenous proteins. Furthermore, disrupted stable compact conformation AR, coupled their where Cα deviations relatively high. Ligand mobility analysis also revealed compounds motion pattern relative optimal binding. We believe findings study significantly aid structure-based design highly dual-inhibitors