4RAQ

Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their pro-drugs as antimalarial agents

Summary for 4RAQ

• Entry DOI: 10.2210/pdb4raq/pdb
• Related: 4RAB 4RAC 4RAD 4RAN 4RAO
• Descriptor: Hypoxanthine-guanine phosphoribosyltransferase, [(2-{[2-(6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl](2-phosphonoethyl)amino}ethoxy)methyl]phosphonic acid, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: hypoxanthine-guanine phosphoribosyltransferase, acyclic nucleoside monophosphonates, malaria, 6-oxopurine phosphoribosyltransferase, 9-[(n-phosphonoethyl-n-phosphonomethoxyethyl)-2-aminoethyl]hypoxanthine, cytoplasmic, 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: 99820.39

Authors

Keough, D.T.,Hockova, D.,Janeba, Z.,Wang, T.-H.,Naesens, L.,Edstein, M.D.,Chavchich, M.,Guddat, L.W. (deposition date: 2014-09-10, release date: 2015-01-07, Last modification date: 2024-02-28)

Primary citation

Keough, D.T.,Hockova, D.,Janeba, Z.,Wang, T.H.,Naesens, L.,Edstein, M.D.,Chavchich, M.,Guddat, L.W.
Aza-acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group As Inhibitors of the Human, Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases and Their Prodrugs As Antimalarial Agents.
J.Med.Chem., 58:827-846, 2015

PubMed Abstract: Hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for antimalarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT), with Ki values as low as 0.08 and 0.01 μM for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza-ANPs exhibit antimalarial activity against Pf lines with IC50 values (0.8-6.0 μM) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors, allowing them to adapt to fit into three binding pockets of the enzyme(s).

PubMed: 25494538
DOI: 10.1021/jm501416t

Experimental method

X-RAY DIFFRACTION (2.53 Å)