Molecular modelling and conformational analysis of a GABAB antagonist

ABSTRACT:In order to determine the structural requirements that are important for GABA binding affinity, a quantum-chemical-based conformational study has been B performed, followed by a similarity analysis which includes 12 GABA analogs. Due B w Ž . to the flexibility of the structures, a semigrid GABA analog 2RS-5,5-dimethyl B x morpholinyl-acetic acid has been used as a template for the amonium moiety in order to help to identify the active conformation. Both in vacuo, and solvent-simulated calculations, for the physiological media modeled as water molecules, have been compared, for this Ž Ž . . Ž . analog, at ab initio G94, 6-31 q G d,p and semiempirical PM3 levels, respectively. On the basis of this comparison, the results of in vacuo PM3 calculations have been chosen for the similarity analysis. We have included, in the calculations, a group of molecules heterogeneous enough to become representative of the different families that can bind to the GABA receptor site. Following their comparison we report the leading characteristics B that can be related to their binding capability and define a pharmacophoric pattern for GABA analogs. The latter is compared with the one previously found for the binding B affinity at the GABA receptor site.

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Theoretical approach to the pharmacophoric pattern of GABAB analogs

Lorenzini

Bruno-Blanch

Estiú

1998

Int. J. Quant. Chem.

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Life-science applications of the Cambridge Structural Database

Taylor

2002

Acta Crystallogr D Biol Crystallogr

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Several studies show that the molecular geometries and intermolecular interactions observed in small-molecule crystal structures are relevant to the modelling of in vivo situations, although the influence of crystal packing is sometimes important and should always be borne in mind. Torsional distributions derived from the Cambridge Structural Database (CSD) can be used to map out potential-energy surfaces and thereby help identify experimentally validated conformational minima of molecules with several rotatable bonds. The use of crystallographic data in this way is complementary to in vacuo theoretical calculations since it gives insights into conformational preferences in condensed-phase situations. Crystallographic data also underpin many molecular-fragment libraries and programs for generating three-dimensional models from two-dimensional chemical structures. The modelling of ligand binding to metalloenzymes is assisted by information in the CSD on preferred coordination numbers and geometries. CSD data on intermolecular interactions are useful in structure-based inhibitor design both in indicating how probable a protein-ligand interaction is and what its geometry is likely to be. They can also be used to guide searches for bioisosteric replacements. Crystallographically derived information has contributed to many life-science software applications, including programs for locating binding 'hot spots' on proteins, docking ligands into enzyme active sites, de novo ligand design, molecular superposition and three-dimensional QSAR. Overall, crystallographic data in general, and the CSD in particular, are very significant tools for the rational design of biologically active molecules.

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Molecular modelling and conformational analysis of a GABAB antagonist

Cited by 2 publications

References 21 publications

Theoretical approach to the pharmacophoric pattern of GABAB analogs

Theoretical approach to the pharmacophoric pattern of GABAB analogs

Life-science applications of the Cambridge Structural Database

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