Approaches to design non-covalent inhibitors for human granzyme B (hGrB)

作者：Kim Mi Sun; Buisson Lauriane A; Heathcote Dean A; Hu Haipeng; Braddock D Christopher; Barrett Anthony G M; Ashton Rickardt Philip G; Snyder James P^*

来源：Organic and Biomolecular Chemistry, 2014, 12(44): 8952-8965.

DOI：10.1039/c4ob01874e

A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand "hot spots". In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (>= 25 mu M IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses.

• 出版日期2014