3D molecular structures

The chirality code of a molecule is based on atomic properties and on the 3D structure. Examples of atomic properties arc partial atomic charges and polarizabilities, which are easily accessible by fast empirical methods contained in the PETRA package. Other atomic properties, calculated by other methods, can in principle be used. It is convenient, however, if the chosen atomic property discriminates as much as possible between non-equivalent atoms. 3D molecular structures are easily generated by the GORINA software package (see Section 2.13), but other sources of 3D structures can be used as well. 

Rusinko A III, J M Skell, R Balducci, C M McGarity and R S Pearlman 1988. CONCORD A. Program fi the Rapid Generation of High Quality 3D Molecular Structures. St Louis, Missouri, The University < Texas at Austin and Tripos Associates. 

Computationally deriving a 3D molecular structure of a given protein using a sequence overlay with a related protein of known structure. 

Molecular modeling itself can be simply described as the computer-assisted calculation, modulation, and visualization of realistic 3D-molecular structures and their physical-chemical properties using force fields/ molecular mechanics. 

Moreover, molecular modeling is one key method of a wide range of computer-assisted methods to analyze and predict relationships between protein sequence, 3D-molecular structure, and biological function (sequence-structure-function relationships). In molecular pharmacology these methods focus predominantly on analysis of interactions between different proteins, and between ligands (hormones, drugs) and proteins as well gaining information at the amino acid and even to atomic level. 

Data Bank (PDB) [56], Computational chemists recognized that these compilations of 3D molecular structures would prove very useful, especially as more pharmaceutically relevant compounds were deposited. The CSD was supported by subscribers, including pharmaceutical companies. On the other hand, the PDB was supported by American taxpayers. 

The increased interest in 3D aspects of organic chemistry and quantitative structure-activity relationship (QSAR) studies has caused an increasing need for a much broader access to 3D molecular structures from experiment or calculation. 

Fig. 17.1. Multivariate characterization with VolSurf descriptors. Molecular Interaction Fields (MIF shaded areas) are computed from the 3D-molecular structure. MIFs are transformed in a table of descriptors, and statistical multivariate analysis is performed.

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

Calculated molecular properties from 3D molecular fields of interaction energies are a novel approach to correlate 3D molecular structures with pharmacodynamic, pharmacokinetic and physico-chemical properties. The novel VolSurf descriptors quantitatively characterize size, shape, polarity, hydrophobicity and the balance between them. 

QMPRPlus was used to generate in silico estimates of log P, aqueous solubility, and human jejunal permeability from 3D molecular structures. The predictive... 

Pearlman, D.A. CONCORD rapid generation of high quality approximate 3D molecular structures. Chem. Des. Automat. News. 1987, 2, 1-7. 

Cruciani et al., used a dynamic physicochemical interaction model to evaluate the interaction energies between a water probe and the hydrophilic and hydrophobic regions of the solute with the GRID force field. The VolSurf program was used to generate a PLS model able to predict log Poet [51] from the 3D molecular structure. 

Pearlman, R.S. (1993) 3D molecular structures generation and use in 3D searching, in 3D QSAR in Drug Design. Theory Methods and Applications, 1st edn (ed. H. Kubinyi), FSCOM Science Publishers, Leiden, pp. 41—79. 

Click on the Convert SMILES button to perform the conversion of the linear SMILES strings into 3D coordinates (SDF format). To browse automatically, click the Start Visualizer button for the systematic viewing of the 3D molecular structures from the chemical library (Fig. 18.3). 

Biochemistry in 3D molecular structure tutorials Self-paced, interactive tutorials based on the Chemscape Chime molecular visualization browser plug-in. 

The basic concept of the identification of structural similarity discussed here could be easily extended for 3D molecular structures. 

All of the above argues for development of expert system approaches for 3D molecular structure determination, and these are expected over 5-10 years, at least for the most studied systems proteins and nucleic acids. 

Quality Approximate 3D Molecular Structures. Information about GONCORD is available at www.tripos.com. 

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