Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
Department of Biochemistry & Biophysics , University of North Carolina at Chapel Hill , 120 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States.
J Chem Inf Model. 2018 Apr 23;58(4):794-815. doi: 10.1021/acs.jcim.7b00455. Epub 2018 Mar 19.
An intense effort is made by pharmaceutical and academic research laboratories to identify and develop selective antagonists for each adenosine receptor (AR) subtype as potential clinical candidates for "soft" treatment of various diseases. Crystal structures of subtypes A and AARs offer exciting opportunities for structure-based drug design. In the first part of the present work, Maybridge HitFinder library of 14400 compounds was utilized to apply a combination of structure-based against the crystal structure of AAR and ligand-based methodologies. The docking poses were rescored by CHARMM energy minimization and calculation of the desolvation energy using Poisson-Boltzmann equation electrostatics. Out of the eight selected and tested compounds, five were found positive hits (63% success). Although the project was initially focused on targeting AAR, the identified antagonists exhibited low micromolar or micromolar affinity against A/A, ARs, or AAR, respectively. Based on these results, 19 compounds characterized by novel chemotypes were purchased and tested. Sixteen of them were identified as AR antagonists with affinity toward combinations of the AR family isoforms (A/A, A/A, A/A/A, and A). The second part of this work involves the performance of hundreds of molecular dynamics (MD) simulations of complexes between the ARs and a total of 27 ligands to resolve the binding interactions of the active compounds, which were not achieved by docking calculations alone. This computational work allowed the prediction of stable and unstable complexes which agree with the experimental results of potent and inactive compounds, respectively. Of particular interest is that the 2-amino-thiophene-3-carboxamides, 3-acylamino-5-aryl-thiophene-2-carboxamides, and carbonyloxycarboximidamide derivatives were found to be selective and possess a micromolar to low micromolar affinity for the A receptor.
制药和学术研究实验室正在努力识别和开发每个腺苷受体 (AR) 亚型的选择性拮抗剂，作为各种疾病“软性”治疗的潜在临床候选药物。AR 和 AAR 的晶体结构为基于结构的药物设计提供了令人兴奋的机会。在本工作的第一部分中，利用 Maybridge HitFinder 库中的 14400 种化合物，应用基于结构的方法和基于配体的方法相结合。对接构象通过 CHARMM 能量最小化和泊松-玻尔兹曼方程静电计算的去溶剂化能进行重新评分。在所选择和测试的八种化合物中，有五种被发现是阳性化合物（成功率为 63%）。尽管该项目最初专注于靶向 AAR，但鉴定出的拮抗剂对 A/A、AR 或 AAR 的亲和力分别为低微摩尔或微摩尔。基于这些结果，购买并测试了 19 种具有新型化学结构的化合物。其中 16 种被鉴定为 AR 拮抗剂，对 AR 家族同工型（A/A、A/A、A/A/A 和 A）的组合具有亲和力。本工作的第二部分涉及数百个 AR 与总共 27 种配体复合物的分子动力学 (MD) 模拟，以解析活性化合物的结合相互作用，这些相互作用仅通过对接计算无法实现。这项计算工作允许预测稳定和不稳定的复合物，分别与有效和无效化合物的实验结果一致。特别有趣的是，2-氨基噻吩-3-甲酰胺、3-酰氨基-5-芳基噻吩-2-甲酰胺和羰基氧代羧基脒衍生物被发现对 A 受体具有选择性，且亲和力为微摩尔至低微摩尔。
