发表机构
Attention Labs; Boston Children’s Hospital and Harvard Medical School; Florida Institute of Technology; Georgia Institute of Technology; Worcester Polytechnic Institute（注意力实验室; 波士顿儿童医院和哈佛医学院; 佛罗里达理工学院; 佐治亚理工学院; 伍斯特理工学院）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究探索基于配体虚拟筛选的最优参数，发现无单一Tanimoto截止值适用所有配体，ECFP8为稳定默认，ECFP4为强主指纹，支持分阶段筛选设计并需专家评审。
AI 中文摘要
基于配体的虚拟筛选依赖于一些通常被视为实现细节的选择，包括相似性阈值、指纹设置和原子不变方案。我们考察了这些选择如何改变针对Enamine库中四种胺能参考配体（阿托莫西汀、安非他酮、米氮平和文拉法辛）的排序搜索的组成。候选集通过化合物加权支架新颖性、归一化香农支架多样性和三种合成可及性的计算估计进行评估。我们首先确定了沿累积Tanimoto排序搜索的配体特异性操作点。然后，我们在匹配的检索深度下比较了五种扩展连通性指纹设置，并将ECFP4与特征类类似物FCSFP4进行了比较。最后，240条记录（对应229个独特结构）由三位对计算评分不知情的化学家独立评分。没有单一的Tanimoto截止值能描述所有四种搜索。ECFP8提供了最稳定的汇总设置，尽管文拉法辛偏好ECFP2。在汇总比较中，ECFP4是更强的主要指纹，而FCSFP4贡献了非冗余的化学空间。个体化学家之间的一致性为中等，平均评分比单一评分更可靠。SCScore与盲法共识的关联最高，但性能因配体而异。这些结果支持一种分阶段筛选设计，其中先采用汇总默认设置，随后进行配体特异性校准和专家评审。
英文摘要
Ligand-based virtual screening depends on choices that are often treated as implementation details, including the similarity threshold, fingerprint setting and atom-invariant scheme. We examined how these choices altered the composition of ranked searches against the Enamine library for four aminergic reference ligands: atomoxetine, bupropion, mirtazapine and venlafaxine. Candidate sets were evaluated by compound-weighted scaffold novelty, normalized Shannon scaffold diversity and three computational estimates of synthetic accessibility. We first identified ligand-specific operating points along cumulative Tanimoto-ranked searches. We then compared five extended-connectivity fingerprint settings at matched retrieval depths and compared ECFP4 with the feature-class analogue FCSFP4. Finally, 240 records, corresponding to 229 unique structures, were scored independently by three chemists who were blinded to the computational scores. No single Tanimoto cutoff described all four searches. ECFP8 provided the most stable pooled setting, although venlafaxine favored ECFP2. ECFP4 was the stronger primary fingerprint in pooled comparisons, whereas FCSFP4 contributed nonredundant chemical space. Agreement among individual chemists was moderate, and the mean rating was more reliable than a single rating. SCScore showed the highest association with the blinded consensus, but performance varied by ligand. These results support a staged screening design in which a pooled default is followed by ligand-specific calibration and expert review.
