ProSPECCTs

The automated comparison of protein-ligand binding sites provides useful insights into yet unexplored site similarities. Various stages of computational and chemical biology research can benefit from this knowledge. The search for putative off-targets and the establishment of polypharmacological effects by comparing binding sites led to promising results for numerous projects. Although many cavity comparison methods are available, a comprehensive analysis to guide the choice of a tool for a specific application is wanting. Moreover, the broad variety of binding site modeling approaches, comparison algorithms, and scoring metrics impedes this choice. Herein, we aim to elucidate strengths and weaknesses of binding site comparison methodologies. A detailed benchmark study is the only possibility to rationalize the selection of appropriate tools for different scenarios. Specific evaluation data sets were developed to shed light on multiple aspects of binding site comparison. An assembly of all applied benchmark sets (ProSPECCTs - Protein Site Pairs for the Evaluation of Cavity Comparison Tools) is made available for the evaluation and optimization of further and still emerging methods. The results indicate the importance of such analyses to facilitate the choice of a methodology that complies with the requirements of a specific scientific challenge.

蛋白质-配体结合位点的自动化比对，可为尚未被探索的位点相似性提供极具价值的研究视角。计算生物学与化学生物学研究的诸多环节均可从该类认知中获益。通过比对结合位点预测潜在脱靶靶点、确立多药理学效应的相关研究，已在众多项目中取得了亮眼成果。
尽管目前已有多种空腔比对方法问世，但目前仍缺乏能够指导研究者针对特定应用场景选择合适工具的系统性分析。此外，结合位点建模方法、比对算法以及评分指标的多样性繁杂，进一步加剧了工具选型的难度。
本文旨在阐明各类结合位点比对方法的优势与局限性。唯有通过详尽的基准测试研究，才能合理地为不同应用场景遴选适配的工具。针对结合位点比对的多个维度，我们构建了专属的评估数据集。本文所整合的全部基准数据集（ProSPECCTs——用于评估空腔比对工具的蛋白质位点对数据集，Protein Site Pairs for the Evaluation of Cavity Comparison Tools）现已对外开放共享，以供后续乃至新兴的比对方法开展评估与优化工作。研究结果证实，此类分析对于助力研究者选择契合特定科学研究需求的比对方法至关重要。