PDBsum entry 1sl3

Blood clotting,hydrolase/inhibitor

PDB id: 1sl3

Contents

Protein chains

276 a.a. *

11 a.a. *

Ligands

170

Waters ×281

* Residue conservation analysis

PDB id:

1sl3

Name:

Blood clotting,hydrolase/inhibitor

Title:

Crystal structue of thrombin in complex with a potent p1 heterocycle- aryl based inhibitor

Structure:

Thrombin. Chain: a. Fragment: alpha-thrombin. Synonym: coagulation factor ii. Hirudin. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: pancreas. Synthetic: yes

Biol. unit:

Dimer (from PQS)

Resolution:

1.81Å R-factor: 0.210 R-free: 0.240

Authors:

M.B.Young,J.C.Barrow,K.L.Glass,G.F.Lundell,C.L.Newton,J.M.Pellicore, K.E.Rittle,H.G.Selnick,K.J.Stauffer,J.P.Vacca,P.D.Williams,D.Bohn, F.C.Clayton,J.J.Cook,J.A.Krueger,L.C.Kuo,S.D.Lewis,B.J.Lucas, D.R.Mcmasters,C.Miller-Stein,B.L.Pietrak

Key ref:

M.B.Young et al. (2004). Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors. J Med Chem, 47, 2995-3008. PubMed id: 15163182 DOI: 10.1021/jm030303e

Date:

05-Mar-04 Release date: 03-Aug-04

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 276 a.a.

Protein chain

P28504  (HIR2_HIRME) -  Hirudin-2 from Hirudo medicinalis

Seq: 65 a.a.

Struc: 11 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

DOI no: 10.1021/jm030303e

J Med Chem 47:2995-3008 (2004)

PubMed id: 15163182

Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.

M.B.Young, J.C.Barrow, K.L.Glass, G.F.Lundell, C.L.Newton, J.M.Pellicore, K.E.Rittle, H.G.Selnick, K.J.Stauffer, J.P.Vacca, P.D.Williams, D.Bohn, F.C.Clayton, J.J.Cook, J.A.Krueger, L.C.Kuo, S.D.Lewis, B.J.Lucas, D.R.McMasters, C.Miller-Stein, B.L.Pietrak, A.A.Wallace, R.B.White, B.Wong, Y.Yan, P.G.Nantermet.

ABSTRACT

In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.