Complementarity between in Silico and Biophysical Screening Approaches in Fragment-Based Lead Discovery against the A2A Adenosine Receptor
Complementarity between in Silico and Biophysical Screening Approaches in Fragment-Based Lead Discovery against the A2A Adenosine Receptor
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DOI：
10.1021/ci4003156
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发表时间：
2013-10-01
影响因子：
5.6
通讯作者：
Carlsson, Jens
中科院分区：
文献类型：
--
作者：
Chen, Dan;Ranganathan, Anirudh;Carlsson, Jens
基于片段的先导化合物发现（FBLD）正在成为药物开发中越来越重要的方法。我们探索了通过 FBLD 中针对 A(2A) 腺苷受体 (A(2A)AR) 的分子对接来补充基于 NMR 的化学库生物物理筛选的潜力，A(2A)AR 是炎症和帕金森病的药物靶点。在基于 NMR 筛选 A(2A)AR 片段库之前，使用针对晶体结构的分子对接来根据预测的亲和力对同一组分子进行排序。分子对接能够预测 NMR 发现的五个正构配体中的四个位于排名前 5% 的库中，这表明基于结构的方法可用于对生物物理筛选的主要命中进行优先排序。此外，通过分子对接排名靠前但未通过基于 NMR 的方法拾取的三个片段被证明是 A2AAR 配体。虽然用于片段筛选的生物物理方法通常仅限于几千种化合物，但对接筛选已扩展到包括 328,000 个市售片段。在放射性配体结合测定中测试了 22 种顶级化合物，其中 14 种是 K-i 值范围为 2 至 240 mu M 的 A(2A)AR 配体。片段的优化以分子动力学模拟和自由能计算为指导。结果阐明了分子对接的优点和缺点，并证明该方法可以作为 FBLD 生物物理筛选的有价值的补充工具。
Fragment-based lead discovery (FBLD) is becoming an increasingly important method in drug development. We have explored the potential to complement NMR-based biophysical screening of chemical libraries with molecular docking in FBLD against the A(2A) adenosine receptor (A(2A)AR), a drug target for inflammation and Parkinson's disease. Prior to an NMR-based screen of a fragment library against the A(2A)AR, molecular docking against a crystal structure was used to rank the same set of molecules by their predicted affinities. Molecular docking was able to predict four out of the five orthosteric ligands discovered by NMR among the top 5% of the ranked library, suggesting that structure-based methods could be used to prioritize among primary hits from biophysical screens. In addition, three fragments that were top-ranked by molecular docking, but had not been picked up by the NMR-based method, were demonstrated to be A2AAR ligands. While biophysical approaches for fragment screening are typically limited to a few thousand compounds, the docking screen was extended to include 328,000 commercially available fragments. Twenty-two top-ranked compounds were tested in radioligand binding assays, and 14 of these were A(2A)AR ligands with K-i values ranging from 2 to 240 mu M. Optimization of fragments was guided by molecular dynamics simulations and free energy calculations. The results illuminate strengths and weaknesses of molecular docking and demonstrate that this method can serve as a valuable complementary tool to biophysical screening in FBLD.