Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Cell Biochem Biophys. 2021 Mar;79(1):25-36. doi: 10.1007/s12013-020-00957-8. Epub 2020 Nov 22.
The dual inhibition of adenosine receptors A1 (A AR) and A2 (A AR) has been considered as an efficient strategy in the treatment of Parkinson's disease (PD). This led to the recent development of a series of methoxy-substituted benzofuran derivatives among which compound 3j exhibited dual-inhibitory potencies in the micromolar range. Therefore, in this study, we seek to resolve the mechanisms by which this novel compound elicits its selective dual targeting against A AR and A AR. Unique to the binding of 3j in both proteins, from our findings, is the ring-ring interaction elicited by Phe275 (→ Phe170) with the benzofuran ring of the compound. As observed, this π-stacking interaction contributes notably to the stability of 3j at the active sites of A and A AR. Besides, conserved active site residues in the proteins such as Ala170 (→ Ala65), Ile173 (→ Ile68), Val191 (→ Val86), Leu192 (→ Leu87), Ala195 (→ Ala90), Met284 (→ Met179), Tyr375 (→ Tyr369), Ile378 (→ Ile372), and His382 (→ His376) were commonly involved with other ring substituents which further complement the dual binding and stability of 3j. This reflects a similar interaction mechanism that involved aromatic (π) interactions. Consequentially, vdW energies contributed immensely to the dual binding of the compound, which culminated in high ΔG that were homogenous in both proteins. Furthermore, 3j commonly disrupted the stable and compact conformation of A and A AR, coupled with their active sites where Cα deviations were relatively high. Ligand mobility analysis also revealed that both compounds exhibited a similar motion pattern at the active site of the proteins relative to their optimal dual binding. We believe that findings from this study with significantly aid the structure-based design of highly selective dual-inhibitors of A and A AR.
腺苷受体 A1（A1AR）和 A2（A2AR）的双重抑制已被认为是治疗帕金森病（PD）的有效策略。这导致了一系列甲氧基取代苯并呋喃衍生物的最近发展，其中化合物 3j 在微摩尔范围内表现出双重抑制活性。因此，在这项研究中，我们试图确定这种新型化合物引发其对 A1AR 和 A2AR 选择性双重靶向的机制。从我们的发现中可以看出，与两种蛋白质的 3j 结合独特的是，化合物的苯并呋喃环与苯并呋喃环之间引起的环-环相互作用。如观察到的，这种π堆积相互作用对 3j 在 A 和 A2AR 的活性部位的稳定性有显著贡献。此外，蛋白质中的保守活性位点残基，如 Ala170（→Ala65）、Ile173（→Ile68）、Val191（→Val86）、Leu192（→Leu87）、Ala195（→Ala90）、Met284（→Met179）、Tyr375（→Tyr369）、Ile378（→Ile372）和 His382（→His376）通常与其他环取代基共同参与，进一步补充了 3j 的双重结合和稳定性。这反映了涉及芳香（π）相互作用的类似相互作用机制。因此，vdW 能量对化合物的双重结合做出了巨大贡献，导致在两种蛋白质中均为高ΔG。此外，3j 通常破坏 A 和 A2AR 的稳定和紧凑构象，以及它们的活性部位，其中 Cα 偏差相对较高。配体迁移分析还表明，与它们的最佳双重结合相比，两种化合物在蛋白质的活性部位都表现出相似的运动模式。我们相信，这项研究的发现将极大地帮助基于结构的高度选择性 A 和 A2AR 双重抑制剂的设计。
