Drug computational models

Most practical implementations of drug-likeness use a computational model which takes as input the molecular structure, together with various properties, and predicts whether the molecule is drug-like or not. Some of these models may be very simple, such as a series of substructural filters. Only those molecules which pass all of these filters are output, Such filters can be used to eliminate molecules that contain inappropriate functionality. 

TABLE 18.1 Human Enzymes Involved in Drug Metabolism That Have Been Computationally Modeled to Date... 

Jones JP, Mysinger M, Korzekwa KR. Computational models for cytochrome P450 a predictive electronic model for aromatic oxidation and hydrogen abstraction. Drug Metab Dispos 2002 30 7-12. 

Bergstrom, C. A. S. Computational models to predict aqueous drug solubility, permeability and intestinal absorption. Exp. Opin. Drug Metab. Toxicol. 2005, 1, 513-527. 

A topic of actuality is the study of receptor proteins and enzymes for which data bases with crystallographic information are now made available. Computer modelling of the active sites of receptors and enzymes are important tools in rational drug design. Principal components and cluster analysis can be applied to the primary... 

On the technical side, many different model building techniques are being explored and utilized. A fundamental constraint on the application of any model is the quality and availability of the data that it is built upon. In drug discovery, where the true data of interest (human in vivo parameters) are difficult to obtain and scarce, in vitro or preclinical in vivo experimental models are used to generate larger data sets and to guide decision-making. Most commonly, computational models are then used to predict these in vitro or preclinical endpoints. 

Prediction of ADME properties should be simple, since the number of descriptors underlying the properties is relatively small, compared to the number associated with effective drug-receptor binding space. In fact, prediction of ADME is difficult The current ADME experimental data reflect a multiplicity of mechanisms, making prediction uncertain. Screening systems for biological activity are typically single mechanisms, where computational models are easier to develop [1],... 

Compounds from traditional drug space ( common drugs —readily available from chemical suppliers), often chosen for studies by academic laboratories for assay validation and computational model-building purposes, can lead to misleading conclusions when the results of such models are applied to real discovery compounds, which most often have extremely low solubilities [16]. 

Computer advances now make these tools as available to the polymer chemist as they are to drug designers. While it is conceptually possible to design a polymer de novo using computer modeling techniques, this remains an optimistic goal. 

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