基于配体、受体和复合物指纹的虚拟筛选方法比较

Comparison of Ligand-,Target Structure-,and Protein-Ligand Interaction Fingerprint-based Virtual Screening Methods

近年来,作为基于配体和基于受体两种方法的补充,以复合物指纹为基础的药物筛选方法相关研究正受到广泛的重视.那么这种新兴的方法相对于传统方法在筛选结果准确率上是否具有优势?同时,由于复合物指纹可以通过复合物结构测定和将相应蛋白和配体进行分子对接两种方式获得,那么基于这两种方式获得的复合物指纹所得的筛选结果准确率是否有显著性差异呢?通过对一系列HIV-1蛋白酶复合物晶体结构同时进行基于配体的相似性搜索、分子对接传统的能量打分、基于复合物晶体结构的复合物指纹的相似性搜索和基于分子对接所得复合物结构的复合物指纹的相似性搜索的筛选比较,结果表明:(1)如果三种方法都是直接基于实验结构,那么复合物指纹和分子对接两种方法都因为是兼顾了受体和配体两个方面,准确率都要高于仅仅基于配体的方法;(2)实际运用中,通过实验测定所有复合物结构并不可行,因此需要进行分子对接才能大量的获得复合物结构并进一步生成相应的复合物指纹,令人兴奋的是,基于此种方式获得的复合物指纹与直接基于实验复合物结构获得的复合物指纹在筛选结果上并无显著性差异,从而可以作为实验复合物指纹筛选方法的有效补充.

Nowadays, as the supplementary of ligand- and target structure-based methods, the Protein-ligand interaction fingerprint-based drug virtual screening methods have attracted more and more attentions. Does such novel method have advantage in improving the screening accuracy compared with the traditional ones？ Also, since the interaction fingerprints can be obtained from the co-crystallized X-ray or molecular docking, is the screening difference based on such two interaction fingerprints significant enough？ In this paper, a set of X-ray structures of HIV-1 protease complexes are used to compare the ranking results achieved by the similarity comparison based on four kinds of scorings, i.e., docking energy score, interaction fingerprints score from X-ray structures as well as molecular docking poses, and finally the molecular fingerprints score. It is clearly shown that （i） when the X-ray structures were used, the quality of ranking by docking energy score or similarity of interaction fingerprints outperforms that by molecular fingerprints, due to that the target structure information and ligand information are all taken into consideration; （ii） Normally in ordinary applications, since it is not feasible to co-crystallize all structures, the complex structures arepredicted by molecular docking and then the fingerprints of the complex are generated. Our study indicated that there is no significant statistically difference between the screening results evaluated by interaction fingerprints scores obtained from the docking poses and the X-ray complex structures. Thus it can be served as an efficient drug virtual screen method complement to the experimental based interaction fingerprints method.