Three‐dimensional computer modeling as an aid to drug design

Abstract

Humblet, C., and G.R. Marshall: Three-dimensional computer modeling as an aid to drug design. Drug Dev. Res. 1:409-434, 1981. Three-dimensional computer graphic systems are an emerging tool in the design of therapeutic compounds. The molecular recognition process involved in drug receptor interaction implies a three-dimensional stereospecificity shared by a set of drugs of similar pharmacological action. In investigating the pharmacophore, it is therefore necessary to go beyond two-dimensional structures by including the description of the spatial properties of drugs. 410 Humblet and MarshallThis review describes both current and potential tools that a graphic computer can support to help the medicinal chemist in his structure-activity puzzle. An outline of the systems presently in use for this purpose and a summary of recent applications is given. Some current developments undertaken in our research group are presented in the field of opiates, GABA, clonidine, antipsychotics, and S-adenosyl-Lmethionine inhibitors.

Modeling of the conformational flexibility and E/Z isomerism of thiazoximic acid and cefotaxime

“…To select a representative subset of these structures for the following higher level of computing, a conformational families clustering analysis was carried out [58]. For the later, two major types of parameters were considered: the relative values of the potential energy and a set of correlated distances [52][53][54][55]. The later required specifying a range of distances between well-chosen pseudoatoms.…”

“…A systematic conformational search was initially performed separately on the Z and E isomers of CFX via a well-tried procedure linking MM and MD [52][53][54][55]. It made use of the Rotor tool of the Discover program and involved the CFF91 force field parameters set [47,56].…”

Chemoinformatics: a history

“…However, even this simple example might represent several hundred distinct molecules if some of the substitutions were optional and if homologous series were involved, with more complex forms of variation meaning that a single Markush structure in a patent can represent not hundreds but hundreds of thousands of distinct molecules. [51][52][53] However, the extension of the existing systems for 2D substructure searching to the 3D context was not completed for more than a decade. Much of this work was carried out in collaboration with CAS and Derwent Information Ltd., the two major providers of chemical patent information, with the result that operational public systems began to appear in the early 1990s.…”

Interactive computer display and analysis of small-molecule crystal structures

“…It assists in interpreting electron density maps (Tsernoglou, Petsko, McQueen & Hermans, 1977), in refining crystal structures ' (Collins, Cotton, Hazen, Meyer & Morimoto, 1975), : and in modelling drug-receptor interactions | i (Humblet & Marshall, 1981;Meyer, Cole, Presta, : Rosenfield & Swanson, 1982). Until now, it has not ' been vigorously applied to the examination of smalli ' : molecule crystal structures.…”