title: Structure-based design and development of functionalized Mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus.
abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 Å upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Dennis
authors.forename: Sandeep
authors.initials: S
authors.lastname: Chhabra
authors.forename: Zhong-Chang
authors.initials: ZC
authors.lastname: Wang
authors.forename: Aaron
authors.initials: A
authors.lastname: Debono
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.forename: Janet
authors.initials: J
authors.lastname: Newman
authors.forename: Noel P
authors.initials: NP
authors.lastname: Pitcher
authors.forename: Raphael
authors.initials: R
authors.lastname: Rahmani
authors.forename: Ben
authors.initials: B
authors.lastname: Cleary
authors.forename: Nicholas
authors.initials: N
authors.lastname: Barlow
authors.forename: Meghan
authors.initials: M
authors.lastname: Hattarki
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Peat
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: James D
authors.initials: JD
authors.lastname: Swarbrick
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004094:Dihydropteroate Synthase / Q000737:chemistry; D017854:Diphosphotransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D005492:Folic Acid / Q000096:biosynthesis*; D006147:Guanine / Q000737:chemistry*; D007477:Ions; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D011622:Pterins / Q000737:chemistry; D013211:Staphylococcus aureus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: C492818:6-hydroxymethyl-7,8-dihydropterin; D007477:Ions; D011622:Pterins; D006147:Guanine; D000255:Adenosine Triphosphate; D005492:Folic Acid; D004094:Dihydropteroate Synthase; D017854:Diphosphotransferases; C019684:2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase