Mettai Merzaka, Daoud Ismail, Mesli Fouzia, Kenouche Samir, Melkemi Nadjib, Kherachi Rania, Belkadi Ahlem
Group of Computational and Pharmaceutical Chemistry LMCE Laboratory, University of Biskra, 07000 Biskra, Algeria.
Department of Matter Sciences, University Mohamed Khider, BP 145 RP, 07000 Biskra, Algeria.
In Silico Pharmacol. 2023 Jan 19;11(1):3. doi: 10.1007/s40203-023-00139-3. eCollection 2023.
Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson's disease. Recently, hMAO-B and hAR Dual-targets inhibitory potential of a novel series of Phenylxanthine derivatives has been established in experimental findings. Hence, the current study examines the interactions between 38 compounds of this series with hMAO-B and hAR targets using different molecular modeling techniques to investigate the binding mode and stability of the formed complexes. A molecular docking study revealed that the compounds ((E)-3-(3-Chlorophenyl)--(4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and ((E)-3-(3-Chlorophenyl)--(3-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acrylamide) had a high affinity (S-score: -10.160 and -7.344 kcal/mol) with the pocket of hMAO-B and hAR targets respectively, and the stability of the studied complexes was confirmed during MD simulations. Also, the MEP maps of compounds and were used to identify the nucleophilic and electrophilic attack regions. Moreover, the bioisosteric replacement approach was successfully applied to design two new analogs of each compound with similar biological activities and low energy scores. Furthermore, ADME-T and Drug-likeness results revealed the promising pharmacokinetic properties and oral bioavailability of these compounds. Thus, compounds , , and their analogs can undergo further analysis and optimization in order to design new lead compounds with higher efficacy toward Parkinson's disease.
The online version contains supplementary material available at 10.1007/s40203-023-00139-3.
单胺氧化酶B和腺苷A2A受体被用作帕金森病的关键靶点。最近，一系列新型苯基黄嘌呤衍生物的人源单胺氧化酶B和人源腺苷A2A受体双靶点抑制潜力已在实验结果中得到证实。因此，本研究使用不同的分子建模技术研究了该系列38种化合物与人源单胺氧化酶B和人源腺苷A2A受体靶点之间的相互作用，以研究形成的复合物的结合模式和稳定性。分子对接研究表明，化合物（（E）-3-（3-氯苯基）-2-（4-（1,3-二甲基-2,6-二氧代-2,3,6,7-四氢-1H-嘌呤-8-基）苯基）丙烯酰胺和（（E）-3-（3-氯苯基）-2-（3-（1,3-二甲基-2,6-二氧代-2,3,6,7-四氢-1H-嘌呤-8-基）苯基）丙烯酰胺）分别与人源单胺氧化酶B和人源腺苷A2A受体靶点的口袋具有高亲和力（S分数：-10.160和-7.344千卡/摩尔），并且在分子动力学模拟期间证实了所研究复合物的稳定性。此外，化合物1和2的分子静电势图用于识别亲核和亲电攻击区域。此外，生物电子等排体替换方法成功应用于设计具有相似生物活性和低能量分数的每种化合物的两种新类似物。此外，药物代谢动力学和药物相似性结果揭示了这些化合物有前景的药代动力学性质和口服生物利用度。因此，化合物1、2及其类似物可以进行进一步分析和优化，以便设计出对帕金森病具有更高疗效的新先导化合物。
在线版本包含可在10.1007/s40203-023-00139-3获取的补充材料。
