PDBsum entry 4tzr

Transferase

PDB id: 4tzr

Contents

Protein chain

461 a.a.

Ligands

UW2

Waters ×128

PDB id:

4tzr

Name:

Transferase

Title:

Calcium-dependent protein kinase 1 from toxoplasma gondii (tgcdpk1) in complex with inhibitor uw1561

Structure:

Calmodulin-domain protein kinase 1. Chain: a. Fragment: unp residues 30-507. Engineered: yes. Mutation: yes

Source:

Toxoplasma gondii. Organism_taxid: 5811. Gene: cdpk1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.209 R-free: 0.242

Authors:

E.A.Merritt

Key ref:

R.S.Vidadala et al. (2016). Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis. J Med Chem, 59, 6531-6546. PubMed id: 27309760

Date:

10-Jul-14 Release date: 27-Aug-14

Protein chain

Q9BJF5  (Q9BJF5_TOXGO) -  Calmodulin-domain protein kinase 1 from Toxoplasma gondii

Seq: 507 a.a.

Struc: 461 a.a.

Enzyme reactions

• Enzyme class: E.C.?

J Med Chem 59:6531-6546 (2016)

PubMed id: 27309760

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.

R.S.Vidadala, K.L.Rivas, K.K.Ojo, M.A.Hulverson, J.A.Zambriski, I.Bruzual, T.L.Schultz, W.Huang, Z.Zhang, S.Scheele, A.E.DeRocher, R.Choi, L.K.Barrett, L.K.Siddaramaiah, W.G.Hol, E.Fan, E.A.Merritt, M.Parsons, G.Freiberg, K.Marsh, D.J.Kempf, V.B.Carruthers, N.Isoherranen, J.S.Doggett, W.C.Van Voorhis, D.J.Maly.

ABSTRACT

New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.