PDBsum entry 5c26

Transferase/inhibitor

PDB id: 5c26

Contents

Protein chain

274 a.a.

Ligands

GLU-VAL-PTR-GLU-SER-PRO

50H

Waters ×183

PDB id:

5c26

Name:

Transferase/inhibitor

Title:

Crystal structure of syk in complex with compound 1

Structure:

Tyrosine-protein kinase syk. Chain: a. Fragment: unp residues 343-635. Synonym: spleen tyrosine kinase,p72-syk. Engineered: yes. Glu-val-ptr-glu-ser-pro. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_taxid: 7108

Resolution:

1.95Å R-factor: 0.186 R-free: 0.215

Authors:

S.Han,J.Chang

Key ref:

F.Lovering et al. (2016). Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free-Energy Perturbation (FEP). Chemmedchem, 11, 217-233. PubMed id: 26381330 DOI: 10.1002/cmdc.201500333

Date:

15-Jun-15 Release date: 07-Oct-15

Protein chain

P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK from Homo sapiens

Seq: 635 a.a.

Struc: 274 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP (Bound ligand (Het Group name = PTR) matches with 76.19% similarity) + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1002/cmdc.201500333

Chemmedchem 11:217-233 (2016)

PubMed id: 26381330

Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free-Energy Perturbation (FEP).

F.Lovering, C.Aevazelis, J.Chang, C.Dehnhardt, L.Fitz, S.Han, K.Janz, J.Lee, N.Kaila, J.McDonald, W.Moore, A.Moretto, N.Papaioannou, D.Richard, M.S.Ryan, Z.K.Wan, A.Thorarensen.

ABSTRACT

There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative to the parent compound and no increase in atom count. Optimization of 17 led to compounds with nanomolar cellular activity.