5L2Y

Factor VIIa in complex with the inhibitor 1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,20-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl] cyclobutane-1-carboxylic acid

PDB DOI: https://doi.org/10.2210/pdb5L2Y/pdb

Classification: Hydrolase/Hydrolase Inhibitor
Organism(s): Homo sapiens
Expression System: Cricetinae
Mutation(s): No

Deposited: 2016-08-02 Released: 2016-09-28
Deposition Author(s): Wei, A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.82 Å
R-Value Free: 0.189
R-Value Work: 0.172
R-Value Observed: 0.173

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors.

Ladziata, V.U., Glunz, P.W., Zou, Y., Zhang, X., Jiang, W., Jacutin-Porte, S., Cheney, D.L., Wei, A., Luettgen, J.M., Harper, T.M., Wong, P.C., Seiffert, D., Wexler, R.R., Priestley, E.S.

(2016) Bioorg Med Chem Lett 26: 5051-5057

PubMed: 27612545 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2016.08.088
Primary Citation of Related Structures:
5L2Y, 5L2Z, 5L30

PubMed Abstract:
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.

Organizational Affiliation

Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States. Electronic address: vladimir.ladziata@bms.com.

Macromolecule Content

Total Structure Weight: 35.37 kDa
Atom Count: 2,871
Modelled Residue Count: 309
Deposited Residue Count: 309
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Coagulation factor VII (Heavy Chain)	A [auth H]	254	Homo sapiens	Mutation(s): 0 Gene Names: F7 EC: 3.4.21.21
UniProt & NIH Common Fund Data Resources
Find proteins for P08709 (Homo sapiens) Explore P08709 Go to UniProtKB: P08709
PHAROS: P08709 GTEx: ENSG00000057593
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08709
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Coagulation factor VII (Light Chain)	B [auth L]	55	Homo sapiens	Mutation(s): 0 Gene Names: F7 EC: 3.4.21.21
UniProt & NIH Common Fund Data Resources
Find proteins for P08709 (Homo sapiens) Explore P08709 Go to UniProtKB: P08709
PHAROS: P08709 GTEx: ENSG00000057593
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08709
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
70D Query on 70D Download Ideal Coordinates CCD File SDF format, chain C [auth H] MOL2 format, chain C [auth H]	C [auth H]	1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7,9,16,19-hexaen-7-yl]cyclobutane-1-carboxylic acid C₃₅ H₃₆ F N₅ O₅ PROYMPSAMYSXNO-WENCNXQZSA-N		Interactions Focus chain C [auth H] Interactions & Density Focus chain C [auth H]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth H] SDF format, chain F [auth H] SDF format, chain G [auth H] SDF format, chain H MOL2 format, chain E [auth H] MOL2 format, chain F [auth H] MOL2 format, chain G [auth H] MOL2 format, chain H	E [auth H], F [auth H], G [auth H], H	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth H] Focus chain F [auth H] Focus chain G [auth H] Focus chain H Interactions & Density Focus chain E [auth H] Focus chain F [auth H] Focus chain G [auth H] Focus chain H
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain I [auth H] SDF format, chain J [auth H] MOL2 format, chain I [auth H] MOL2 format, chain J [auth H]	I [auth H], J [auth H]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain I [auth H] Focus chain J [auth H] Interactions & Density Focus chain I [auth H] Focus chain J [auth H]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain D [auth H] MOL2 format, chain D [auth H]	D [auth H]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain D [auth H] Interactions & Density Focus chain D [auth H]

Binding Affinity Annotations
ID	Source	Binding Affinity
70D	Binding MOAD: 5L2Y	Ki: 0.14 (nM) from 1 assay(s)
70D	BindingDB: 5L2Y	Ki: 0.14 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.82 Å
R-Value Free: 0.189
R-Value Work: 0.172
R-Value Observed: 0.173
Space Group: P 4₁ 2₁ 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 95.39	α = 90
b = 95.39	β = 90
c = 117.22	γ = 90

Software Package:

Software Name	Purpose
BUSTER-TNT	refinement
PDB_EXTRACT	data extraction
XDS	data reduction
Aimless	data scaling
AMoRE	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-09-28

Deposition Author(s):

Wei, A.

Revision History (Full details and data files)

Version 1.0: 2016-09-28
Type: Initial release
Version 1.1: 2016-10-12
Changes: Database references
Version 1.2: 2023-10-04
Changes: Data collection, Database references, Derived calculations, Refinement description