Irwin John J, Shoichet Brian K, Mysinger Michael M, Huang Niu, Colizzi Francesco, Wassam Pascal, Cao Yiqun
Department of Pharmaceutical Chemistry, Byers Hall, Box 2550, University of California San Francisco, San Francisco, California 94158-2330, USA.
J Med Chem. 2009 Sep 24;52(18):5712-20. doi: 10.1021/jm9006966.
Molecular docking is the most practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCK Blaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCK Blaster recapitulates the crystal ligand pose within 2 A rmsd 50-60% of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5% of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5% of 100 property-matched decoys while also posing within 2 A rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available at http://blaster.docking.org .
分子对接是利用蛋白质结构进行配体发现的最实用方法，但该技术仍存在重要缺陷，使其难以大规模应用。因此，我们创建了一个专家系统DOCK Blaster，以研究完全自动化的可行性。该方法只需一个PDB代码，有时还需要一个配体结构，仅凭这些就能对大型文库进行全面筛选。一个关键特性是自我评估，它使用姿态保真度和富集度来估计自动筛选结果的预期可靠性。与常见基准相比，DOCK Blaster在50 - 60%的时间内能够在2 Å均方根偏差内重现晶体配体姿态；虽不如专家，但也值得尊重。在一半的时间里，配体在随机选择的100个物理匹配诱饵中也排名前5%。我们进行了进一步测试，最终对7755个符合条件的PDB结构进行了研究。在1398个案例中，重新对接的配体在100个属性匹配诱饵中排名前5%，同时姿态偏差也在2 Å均方根偏差内，这表明无监督的前瞻性对接是可行的。可通过http://blaster.docking.org获取DOCK Blaster。
