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PDBsum entry 3d7b
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References listed in PDB file
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Key reference
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Title
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Morpholino, Piperidino, And pyrrolidino derivatives of pyrimidine nucleosides as inhibitors of ribonuclease a: synthesis, Biochemical, And crystallographic evaluation.
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Authors
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A.Samanta,
D.D.Leonidas,
S.Dasgupta,
T.Pathak,
S.E.Zographos,
N.G.Oikonomakos.
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Ref.
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J Med Chem, 2009,
52,
932-942.
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PubMed id
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Abstract
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Six 5'-deoxy-5'-morpholine, piperidine, and pyrrolidine of pyrimidine
nucleosides have been synthesized and characterized. Their inhibitory action to
ribonuclease A has been studied by biochemical analysis and X-ray
crystallography. These compounds are moderate inhibitors of RNase A with
mid-to-upper micromolar inhibition constants (K(i)). The high resolution X-ray
crystal structures of the RNase A-inhibitor complexes have shown that all
inhibitors bind at the enzyme catalytic cleft with the pyrimidine nucleobase at
the B(1)R(2) subsites while the 5' group binds away from the main subsite P(1),
where P-O(5') bond cleavage occurs, toward the solvent close to subsite P(0).
Structure-activity relationship analysis has demonstrated that the compounds
with the larger group in the 5' position are more potent. Comparative structural
analysis of these RNase A complexes with other similar RNase A-ligand complexes
provides a structural explanation of their potency and suggests ways to improve
their efficiency and selectivity. These inhibitors can be the starting point for
the development of compounds that can be used as pharmaceuticals against
pathologies associated with RNase A homologues such as human angiogenin, which
is implicated in tumor induced neovascularization.
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