WIZARD: AI in conformational analysis

Dolata, Daniel P.; Leach, Andrew R.; Prout, Keith

doi:10.1007/bf01680558

Cited by 83 publications

(30 citation statements)

References 23 publications

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“…Other knowledge-based approaches have previously been described in the literature. The Chem-X 3D Builder [48], WIZARD and COBRA [49][50][51][52] are based on conformational templates and sets of rules derived from molecular mechanics. The program AIMB [53] uses, similar to the present approach, crystallographic data as input.…”

Section: Discussionmentioning

confidence: 99%

A fast and efficient method to generate biologically relevant conformations

Klebe

Mietzner

1994

J Computer-Aided Mol Des

164

122

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Mutual binding between a ligand of low molecular weight and its macromolecular receptor demands structural complementarity of both species at the recognition site. To predict binding properties of new molecules before synthesis, information about possible conformations of drug molecules at the active site is required, especially if the 3D structure of the receptor is not known. The statistical analysis of small-molecule crystal data allows one to elucidate conformational preferences of molecular fragments and accordingly to compile libraries of putative ligand conformations. A comparison of geometries adopted by corresponding fragments in ligands bound to proteins shows similar distributions in conformations space. We have developed an automatic procedure that generates different conformers of a given ligand. The entire molecule is decomposed into its individual ring and open-chain torsional fragments, each used in a variety of favorable conformations. The latter ones are produced according to the library information about conformational preferences. During this building process, an extensive energy ranking is applied. Conformers ranked as energetically favorable are subjected to an optimization in torsion angle space. During minimization, unfavorable van der Waals interactions are removed while keeping the open-chain torsion angles as close as possible to the experimentally most frequently observed values. In order to assess how well the generated conformers map conformation space, a comparison with experimental data has been performed. This comparison gives some confidence in the efficiency and completeness of this approach. For some ligands that had been structurally characterized by protein crystallography the program was used to generate sets of some 10 to 100 conformers. Among these, geometries are found that fall convincingly close to the conformations actually adopted by these ligands at the binding site.

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Section: Discussionmentioning

confidence: 99%

A fast and efficient method to generate biologically relevant conformations

Klebe

Mietzner

1994

J Computer-Aided Mol Des

164

122

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“…For example, in the entity connectivity graph in Fig. 9 the order in which the entities are joined would be [1,2,5,9,10,3,6,4,7,11,8]. The entity sequence is then converted into the equivalent unit join-order list, ensuring that each unit always adjoins at least one previous unit in the list.…”

Section: Resultsmentioning

confidence: 99%

“…WIZARD has been described previously [1]. In the WIZARD analysis of a molecule, specified by its atom types and connectivity, important conformational features such as bond orders, stereocentres, rings, aromaticity etc.…”

Section: Introductionmentioning

confidence: 99%

Automated conformational analysis: Algorithms for the efficient construction of low-energy conformations

Leach¹,

Prout²,

Dolata³

1990

J Computer-Aided Mol Des

Self Cite

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The method of constructing low-energy conformations using template joining can provide an efficient means of searching the conformational space of molecules. The simplest algorithm to perform this task would construct each potential conformation from scratch. However, new algorithms, some of which use techniques from Artificial Intelligence, have been developed which can greatly improve the efficiency of this approach.

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“…This technique allows, after confermational analysis, the molecular structure matching of a large number of compounds at the same time, thus providing valuable insight in conformation-activity relationships. When artificial intelligence and expert systems in conformational analysis are coming of age in the nottoo-far-away future the power of computerassisted drug design will further increase [12].…”

Section: (4) 1991mentioning

confidence: 99%

The role of medicinal chemistry in drug research

Soudijn

1991

Pharmaceutisch Weekblad Scientific Edition

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Classical medicinal chemistry, that is molecular modifications of existing bioactive compounds, leading to me-too drugs with value added and often to me-too drugs which will never reach the market or to drugs in another pharmacological field than that originally intended, will be with us for a long time to come. The ultimate goal, however, is of course rational or at least semi-rational drug design. In some instances this goal seems to have already been reached as in the case of angiotensin-converting enzyme inhibitors and H2 antagonists. In the (near) future results from the steady progress in molecular biology in combination with computer-assisted drug modelling--possibly coupled with artificial intelligence techniques--will help the medicinal chemist in his efforts to attain this goal.

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WIZARD: AI in conformational analysis

Cited by 83 publications

References 23 publications

A fast and efficient method to generate biologically relevant conformations

A fast and efficient method to generate biologically relevant conformations

Automated conformational analysis: Algorithms for the efficient construction of low-energy conformations

The role of medicinal chemistry in drug research

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