Farnesyl pyrophosphate synthase enantiospecificity with a chiral risedronate analog, [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501): Synthetic, structural, and modeling studies.
The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantiomer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3, which was also evaluated for predictive ability in calculations of the known configurations of risedronate, zoledronate, and minodronate complexed in the active site of hFPPS. In comparison with these structures, the 8 complex exhibited certain differences, including the presence of only one Mg(2+), which could contribute to its 100-fold higher IC(50). An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.
Deprèle
Sylvine
S
Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
Kashemirov
Boris A
BA
Hogan
James M
JM
Ebetino
Frank H
FH
Barnett
Bobby L
BL
Evdokimov
Artem
A
McKenna
Charles E
CE
D000465:Algorithms; D001665:Binding Sites; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D000068296:Risedronic Acid; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000077211:Zoledronic Acid
C529908:(6,7-dihydro-5H-cyclopenta(c)pyridin-7-yl(hydroxy)methylene)bis(phosphonic acid); D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D063065:Organophosphonates; D011725:Pyridines; C087958:YM 529; D000077211:Zoledronic Acid; D051231:Farnesyltranstransferase; D008274:Magnesium; D000068296:Risedronic Acid; D012968:Etidronic Acid