PDBsum entry 6pl1

Transferase

PDB id: 6pl1

Contents

Protein chain

290 a.a.

Ligands

OOJ

Waters ×57

References listed in PDB file

Key reference

• Title: Lead identification and characterization of htrka type 2 inhibitors.
• Authors: G.Subramanian, Y.Zhu, S.J.Bowen, N.Roush, J.A.White, D.Huczek, T.Zachary, C.Javens, T.Williams, A.Janssen, A.Gonzales.
• Ref.: Bioorg Med Chem Lett, 2019, 29, 126680. [DOI no: 10.1016/j.bmcl.2019.126680]
• PubMed id: 31610943

Abstract

Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.