Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface

摘要: Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means a systematic deconstruction lead-like inhibitors pVHL:HIF-1α interaction into their component fragments. Using biophysical techniques commonly employed screening, could only detect binding fragments that violate Rule Three, are more complex than those typically screened against classical druggable targets, occupy two adjacent subsites at interface rather just one. Analyses based on ligand group lipophilicity efficiency anchored were applied dissect individual probe hot spots. The implications our findings targeting protein fragment-based approaches discussed.