5T4S

Novel Approach of Fragment-Based Lead Discovery applied to Renin Inhibitors

Summary for 5T4S

• Entry DOI: 10.2210/pdb5t4s/pdb
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, 1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE, ... (7 entities in total)
• Functional Keywords: protein-ligand complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 75532.52

Authors

Snell, G.P.,Behnke, C.A.,Okada, K.,Oki, H.,Sang, B.C.,Lane, W. (deposition date: 2016-08-30, release date: 2016-10-26, Last modification date: 2024-11-06)

Primary citation

Tawada, M.,Suzuki, S.,Imaeda, Y.,Oki, H.,Snell, G.,Behnke, C.A.,Kondo, M.,Tarui, N.,Tanaka, T.,Kuroita, T.,Tomimoto, M.
Novel approach of fragment-based lead discovery applied to renin inhibitors.
Bioorg.Med.Chem., 24:6066-6074, 2016

PubMed Abstract: A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3 (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures. Second, we created a new and smaller scaffold, which better occupied the identified essential S3 and S3 sites, by utilizing library synthesis with high-throughput chemistry. We then revisited the S1 site and efficiently explored a good building block attaching to the scaffold with library synthesis. In the library syntheses, the binding modes of each pivotal compound were determined and confirmed by X-ray crystallography and the library was strategically designed by structure-based computational approach not only to obtain a more active compound but also to obtain informative Structure Activity Relationship (SAR). As a result, we obtained a lead compound offering synthetic accessibility as well as the improved in vitro ADMET profiles. The fragments and compounds possessing a characteristic interaction pattern provided new structural insights into renin's active site and the potential to create a new generation of renin inhibitors. In addition, we demonstrated our FBDD strategy integrating highly sensitive biochemical assay, X-ray crystallography, and high-throughput synthesis and in silico library design aimed at fragment morphing at the initial stage was effective to elucidate a pocket profile and a promising lead compound.

PubMed: 27720325
DOI: 10.1016/j.bmc.2016.09.065

Experimental method

X-RAY DIFFRACTION (2.64 Å)