4Q1N

Structure-based design of 4-hydroxy-3,5-substituted piperidines as direct renin inhibitors

PDB DOI: https://doi.org/10.2210/pdb4Q1N/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Homo sapiens
Mutation(s): No

Deposited: 2014-04-04 Released: 2014-08-06
Deposition Author(s): Schiering, N., D'Arcy, A., Irie, O., Yokokawa, F.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.09 Å
R-Value Free: 0.189
R-Value Work: 0.169
R-Value Observed: 0.170

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.

Ehara, T., Irie, O., Kosaka, T., Kanazawa, T., Breitenstein, W., Grosche, P., Ostermann, N., Suzuki, M., Kawakami, S., Konishi, K., Hitomi, Y., Toyao, A., Gunji, H., Cumin, F., Schiering, N., Wagner, T., Rigel, D.F., Webb, R.L., Maibaum, J., Yokokawa, F.

(2014) ACS Med Chem Lett 5: 787-792

PubMed: 25050166 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/ml500137b
Primary Citation of Related Structures:
4PYV, 4Q1N

PubMed Abstract:
A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

Organizational Affiliation

Novartis Institutes for BioMedical Research , Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan.

Macromolecule Content

Total Structure Weight: 76.26 kDa
Atom Count: 5,752
Modelled Residue Count: 672
Deposited Residue Count: 680
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Renin	A, B	340	Homo sapiens	Mutation(s): 0 Gene Names: REN EC: 3.4.23.15
UniProt & NIH Common Fund Data Resources
Find proteins for P00797 (Homo sapiens) Explore P00797 Go to UniProtKB: P00797
PHAROS: P00797 GTEx: ENSG00000143839
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P00797
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
2Y9 Query on 2Y9 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain J [auth B] MOL2 format, chain F [auth A] MOL2 format, chain J [auth B]	F [auth A], J [auth B]	(3S,4R,5R)-N-cyclopropyl-N'-[(2R)-1-ethoxy-4-methylpentan-2-yl]-4-hydroxy-N-[5-(propan-2-yl)pyridin-2-yl]piperidine-3,5-dicarboxamide C₂₆ H₄₂ N₄ O₄ YOVGCKBDPOHLAV-CNIHBODFSA-N		Interactions Focus chain F [auth A] Focus chain J [auth B] Interactions & Density Focus chain F [auth A] Focus chain J [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain I [auth B] MOL2 format, chain D [auth A] MOL2 format, chain I [auth B]	D [auth A], I [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain D [auth A] Focus chain I [auth B] Interactions & Density Focus chain D [auth A] Focus chain I [auth B]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A]	E [auth A]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain G [auth B] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain G [auth B] MOL2 format, chain H [auth B]	C [auth A], G [auth B], H [auth B]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain G [auth B] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain G [auth B] Focus chain H [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
2Y9	BindingDB: 4Q1N	IC50: min: 0.2, max: 2 (nM) from 3 assay(s)
2Y9	Binding MOAD: 4Q1N	IC50: 0.2 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.09 Å
R-Value Free: 0.189
R-Value Work: 0.169
R-Value Observed: 0.170
Space Group: P 2₁ 3

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 140.854	α = 90
b = 140.854	β = 90
c = 140.854	γ = 90

Software Package:

Software Name	Purpose
MAR345	data collection
PHASER	phasing
BUSTER	refinement
XDS	data reduction
XSCALE	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-08-06

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-08-06
Type: Initial release
Version 1.1: 2017-11-22
Changes: Refinement description
Version 1.2: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Derived calculations, Structure summary