在这项工作中,我们提供了一个案例研究,以探讨与寻找受体的新分子相关的挑战,该受体已被深入研究,并拥有丰富的化学信息。具体来说,我们应用之前描述的方案,在配体结合位点引入明确的水分子,从市售的eMolecules数据库中前瞻性筛选超过250万种药物样和铅样化合物,以寻找腺苷A2A受体(A2AAR)的新型结合剂.基于高配体效率和高新颖性(任何A2AAR测试化合物的Tanimoto系数≤0.25),总共选择了71种化合物用于购买和生化测定。然后在放射性配体结合测定中测试这些分子对腺苷A2A受体的亲和力。我们确定了在10μM浓度下满足~50%放射性配体置换标准的两个命中。接下来,我们选择了另外8个预测与Asn2536.55(A2AAR的结合袋中的关键相互作用残基)进行双齿相互作用的新分子。这八个分子都没有发现有活性。基于这些结果,我们讨论了基于结构的方法的优势以及与为充分探索的靶标寻找化学新分子相关的挑战。
In this work, we present a
case study to explore the challenges associated with finding novel molecules for a receptor that has been studied in depth and has a wealth of chemical information available. Specifically, we apply a previously described protocol that incorporates explicit water molecules in the ligand binding site to prospectively screen over 2.5 million drug-like and lead-like compounds from the commercially available eMolecules database in search of novel binders to the adenosine A2A receptor (A2AAR). A total of seventy-one compounds were selected for purchase and biochemical assaying based on high ligand efficiency and high novelty (Tanimoto coefficient ≤0.25 to any A2AAR tested compound). These molecules were then tested for their affinity to the adenosine A2A receptor in a radioligand binding assay. We identified two hits that fulfilled the criterion of ~50 % radioligand displacement at a concentration of 10 μM. Next we selected an additional eight novel molecules that were predicted to make a bidentate interaction with Asn2536.55, a key interacting residue in the binding pocket of the A2AAR. None of these eight molecules were found to be active. Based on these results we discuss the advantages of structure-based methods and the challenges associated with finding chemically novel molecules for well-explored targets.