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Abstract：
Virtual screening (VS) is a routine method to evaluate chemical libraries for lead identification. Therefore, the selection of appropriate protein structures for VS is an essential prerequisite to identify true actives during docking. But the presence of several crystal structures of the same protein makes it difficult to select one or few structures rationally for screening. Therefore, a computational prioritization protocol has been developed for shortlisting crystal structures that identify true active molecules with better efficiency. As identification of small-molecule inhibitors is an important clinical requirement for the T790M/L858R (TMLR) EGFR mutant, it has been selected as a case study. The approach involves cross-docking of 21 co-crystal ligands with all the structures of the same protein to select structures that dock non-native ligands with lower RMSD. The cross docking performance was then correlated with ligand similarity and binding-site conformational similarity. Eventually, structures were shortlisted by integrating cross-docking performance, and ligand and binding-site similarity. Thereafter, binding pose metadynamics was employed to identify structures having stable co-crystal ligands in their respective binding pockets. Finally, different enrichment metrics like BEDROC, RIE, AUAC, and EF1% were evaluated leading to the identification of five TMLR structures (5HCX, 5CAN, 5CAP, 5CAS, and 5CAO). These structures docked a number of non-native ligands with low RMSD, contain structurally dissimilar ligands, have conformationally dissimilar binding sites, harbor stable co-crystal ligands, and also identify true actives early. The present approach can be implemented for shortlisting protein targets of any other important therapeutic kinases.
摘要：
虚拟筛选（VS）是评估用于铅鉴定的化学库的常规方法。因此,为VS选择合适的蛋白质结构是在对接过程中鉴定真正活性物的必要先决条件。但是同一蛋白质的几个晶体结构的存在使得难以合理地选择一个或几个结构进行筛选。因此,已经开发了一种计算优先方案，用于入围晶体结构，以更好的效率识别真正的活性分子。由于小分子抑制剂的鉴定是T790M/L858R（TMLR）EGFR突变体的重要临床要求，它已被选为案例研究。该方法涉及21个共晶配体与相同蛋白质的所有结构的交叉对接,以选择对接具有较低RMSD的非天然配体的结构。然后将交叉对接性能与配体相似性和结合位点构象相似性相关联。最终,结构通过整合交叉对接性能入围，以及配体和结合位点的相似性。此后,结合位元动力学（BPMD）用于鉴定在其各自的结合袋中具有稳定的共晶配体的结构。最后,不同的富集指标，如BEDROC，RIE,AUAC,和EF1％进行了评估，从而鉴定了五个TMLR结构（5HCX，5CAN,5CAP,5CAS和5CAO)。这些结构对接了许多具有低RMSD的非天然配体，含有结构上不同的配体，具有构象不同的结合位点，具有稳定的共晶配体，并且还可以早期鉴定真正的活性物质。本方法可用于任何其他重要治疗性激酶的短列表蛋白质靶标。本文受版权保护。保留所有权利。
