A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists

In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 1993-02, Vol.7 (1), p.83-102
Main Authors: Martin, Y C, Bures, M G, Danaher, E A, DeLazzer, J, Lico, I, Pavlik, P A
Format: Article
Language:English
Subjects:
Algorithms
Benzodiazepines - chemistry
Binding Sites
Dopamine Agents - chemistry
Models, Molecular
Molecular Conformation
Molecular Structure
Software
Structure-Activity Relationship
Thermodynamics
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Summary:In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first generate and optimize all low-energy conformations by any suitable method. For each conformation we then use ALADDIN to calculate the location of points to be considered as part of the superposition. These points include atoms in the molecule and projections from the molecule to hydrogen-bond donors and acceptors or charged groups in the binding site. These positions and the relative energy of each conformation are the input to our new program DISCO. It uses a clique-detection method to find superpositions that contain at least one conformation of each molecule and user-specified numbers of point types and chirality. DISCO is fast; for example, it takes about 1 min CPU to propose pharmacophores from 21 conformations of seven molecules. We typically run DISCO several times to compare alternative pharmacophore maps. For D2 dopamine agonists DISCO shows that the newer 2-aminothiazoles fit the traditional pharmacophore. Using site points correctly identifies the bioactive enantiomers of indoles to compare with catechols whereas using only ligand points leads to selecting the inactive enantiomer for the pharmacophore map. In addition, DISCO reproduces pharmacophore maps of benzodiazepines in the literature and proposes subtle improvements. Our experience suggests that clique-detection methods will find many applications in computational chemistry and computer-assisted molecular design.
ISSN:0920-654X
1573-4951
DOI:10.1007/bf00141577