Design and synthesis of inhibitors of adenosine and AMP deaminases

Organic Letters

Volumn 3, Issue 6, 2001, Pages 839-842

  Bojack, Guido ^a   Earnshaw, Christopher G ^a   Klein, Robert ^a   Lindell, Stephen D ^a   Lowinski, Christian ^a   Preuss, Rainer ^a  

^a BayerCropScience GmbH Chemistry Frankfurt   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DEAMINASE; ADENOSINE MONOPHOSPHATE DEAMINASE; ENZYME INHIBITOR; NUCLEOSIDE; NUCLEOTIDE;

ANIMAL; ARTICLE; CALORIMETRY; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DRUG ANTAGONISM; DRUG DESIGN; MAMMAL; SYNTHESIS; THERMODYNAMICS;

ADENOSINE DEAMINASE; AMP DEAMINASE; ANIMALS; CALORIMETRY; DRUG DESIGN; ENZYME INHIBITORS; MAMMALS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; NUCLEOSIDES; NUCLEOTIDES; THERMODYNAMICS;

EID: 0035932612     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol006992v     Document Type: Article

References (25)

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14. m value of 35 μM and its assay concentration was 60 μM.
15. Enthalpy of Hydration Calculations: Calculations were performed using the AMI Hamiltonian in VAMP (Clark, T.; Alex, A.; Beck, B.; Chandrasekhar, J.; Gedeck, P.; Horn, A.; Hutter, M.; Rauhut, G.; Sauer, W.; Steinke, T. VAMP-version 7.0, Erlangen, 1998, distributed by Oxford Molecular Limited) on a model system in which a methyl group replaced the sugar ring. An aqueous environment was simulated using the SCRF method (
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17. f(aglycone): ref 8 and Le, V.-D. Ph.D. Thesis, University of London, 1997, p 26) as it makes it easier to see whether the hydration reactions are likely to be exo- or endothermic. No entropic or explicit hydrogen bonding factors are taken into account. The absolute values of the enthalpy of hydration are consequently only approximate, but are adequate for comparisons of similar structures (Table 1). For related calculations carried out by other workers, see: Erion, M. D.; Reddy, M. R. J. Am. Chem. Soc. 1998, 120, 3295.
18. ADA Binding Energy Calculations: Force-field calculations were performed using an augmented AMBER force field (Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S.; Weiner, P. J. Am. Chem. Soc. 1984, 106, 765).
19. 7 was taken from the Protein Data Bank
20. (entry 2ADA; Berman H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat T. N.; Weissig, H.; Shindyalov I. N.; Bourne P. E. Nucl. Acids Res. 2000, 28, 235). Only those residues (including amino acids, water molecules and the zinc ion) with at least one atom within 8 Å of any atom of the complexed ligand 6-hydroxy-1,6-dihydropurine ribonucleoside (9) were included in the calculations. The geometries of the covalent hydrates derived from structures 11-16 were fully optimised by force-field methods before being docked into the binding site, which had previously been occupied by compound 9. The optimizations of the enzyme-ligand complexes were performed in dihedral space by permitting rotation of specified bonds and free translation and rotation of specified molecules in the system. The specified molecules were the docked ligand and the water molecules HOH 402, 415, 417, 437, and 438 (using the numbering in the PDB file 2ADA). The specified bonds were all of the rotatable single bonds in the corresponding ligand as well as those of the side chains of amino acids Asp 19, Leu 58, Phe 61, Phe 65, Ser 103, Leu 106, Met 155, Ala 183, His 214, Glu 217, His 238, Asp 295, and Cys 514. The X-ray structure served as a reference geometry to compute conformational energies due to geometry changes of the enzyme upon binding of a ligand. Conformational energies of the ligands were determined relative to their fully optimized geometries. The interaction energy was calculated as the sum of the van der Waals and electrostatic interactions between a ligand and the enzyme. Water molecules were treated as part of the enzyme. The binding energies (BE) were then computed by adding together the interaction energy, the conformational energy of the enzyme, and the conformational energy of the ligand. Solvation effects and entropic contributions were not taken into account. The resulting BEs are only an approximate measure of a ligand's binding affinity and cannot be directly compared to the free energy of binding, but the difference between the BEs of any two ligands indicates which should bind most strongly. Therefore, the results are expressed as a relative binding energy which was calculated by subtracting the BE for compound 9 from the BE for each specific compound (Table 1).
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25. 2O) δ 9.37 (0.1H, s, H-8 of 16), 6.33 (0.9H, d, J = 2.5 Hz, H-8 of 18), 5.41 (0.1H, d, J = 6.2 Hz, H-1′of 16), 5.16 (0.9H, dd, J = 2.5 and 6.5 Hz, H-1′of 18), 4.74 (1H, m, H-2′), 4.40 (0.1H, t, J = 6 Hz, H-3′ of 16), 4.35 (0.9H, m, H-3′ of 18), 4.17 (1H, m, H-4′), 3.68-3.85 (2H, m, H-5′); m/z (electrospray) 287 (M + H of 18, 100%), 269 (M + H of 16, 20%).