Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA)Atomic coordinates of the kinase domain of hTrkA. Ligand have been deposited in Protein Data Bank (PDB) under PDB codes 1: 6PMB; 3: 6PMA; 5: 6PME; 6: 6PMC.The manuscript was written by G. S. All authors have given approval to the final version of the manuscript.All experimental procedures are available as part of the ESI in ref. 23–25.Electronic supplementary information (ESI) available: Computational workflow and X-ray data collection and structure determination details. See DOI: 10.1039/c9md00554d

Autor:	Subramanian, Govindan, Vairagoundar, Rajendran, Bowen, Scott J., Roush, Nicole, Zachary, Theresa, Javens, Christopher, Williams, Tracey, Janssen, Ann, Gonzales, Andrea
Zdroj:	MedChemComm; 2020, Vol. 11 Issue: 3 p370-377, 8p
Abstrakt:	In silicovirtual screening followed by in vitrobiochemical, biophysical, and cellular screening resulted in the identification of distinctly different hTrkA kinase domain inhibitor scaffolds. X-ray structural analysis of representative inhibitors bound to hTrkA kinase domain defined the binding mode and rationalized the mechanism of action. Preliminary assessment of the sub-type selectivity against the closest hTrkB isoform, and early ADME guided the progression of select inhibitor leads in the screening cascade. The possibility of the actives sustaining to known hTrkA resistance mutations assessed in silicooffers initial guidance into the required multiparametric lead optimization to arrive at a clinical candidate.
Databáze:	Supplemental Index
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