5BSK

Human HGPRT in complex with (S)-HPEPG, an acyclic nucleoside phosphonate

Summary for 5BSK

• Entry DOI: 10.2210/pdb5bsk/pdb
• Related: 5BRN
• Descriptor: Hypoxanthine-guanine phosphoribosyltransferase, (2-{[(2S)-1-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-hydroxypropan-2-yl]oxy}ethyl)phosphonic acid, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: hypoxanthine-guanine-phosphoribosyltransferase, malaria, acyclic nucleoside phosphonates, inhibitors, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P00492
• Total number of polymer chains: 4
• Total formula weight: 99495.04

Authors

Keough, D.T.,Guddat, L.W.,Kaiser, M.M.,Hockova, D.,Wang, T.-H.,Janeba, Z. (deposition date: 2015-06-02, release date: 2015-09-23, Last modification date: 2023-09-27)

Primary citation

Kaiser, M.M.,Hockova, D.,Wang, T.H.,Dracinsky, M.,Postova-Slavetinska, L.,Prochazkova, E.,Edstein, M.D.,Chavchich, M.,Keough, D.T.,Guddat, L.W.,Janeba, Z.
Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6-Oxopurine Phosphoribosyltransferases.
Chemmedchem, 10:1707-1723, 2015

PubMed Abstract: Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG.

PubMed: 26368337
DOI: 10.1002/cmdc.201500322

Experimental method

X-RAY DIFFRACTION (2.61 Å)