Chemical validation

A fraction of our in-house -8500 ATP-site competitor compounds have been profiled in a number of cellular assays for toxicity, solubility, and permeability. Nontoxic, soluble, permeable compounds have been gathered into a subset of the main library, which we call the validation library . The validation library currently 

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One of the most compelling targets in the polyamine biosynthesis pathway has been S-adenosylmethionine decarboxylase (SAM-DC). This target was chemically validated with the discovery of trypanocidal activity of MDL-73811 nearly two decades ago. Work to understand the unique kinetics for inhibition of this enzyme in T. brucei has shown that a catalytically... 

Stein-Gerlach. Thanks also to Rathe Klebl for all the support. We are thankful for the financial support from the BM B F and our investors for establishing the chemical validation and KinaTor technologies. 

Biochemical and Physico-Chemical Validation of Protein Complexes... 

A detailed kinetic model for n-butane combustion has also been reported by Kojima [234] comprising 700 reversible reactions. Although this may prove to be a useful development, it has not been the subject of chemical validation, having been used only to simulate ignition delays for n-butane in a shock tube and in a rapid compression machine. In the absence of complementary chemical tests, the prediction of ignition delay really constitutes an application rather than a test of a comprehensive kinetic scheme. 

The origins of the subject stem from considerations of the stability of such systems and the mathematical analysis of the differential equations that describe them. It has developed by progressively increasing the chemical complexity of the descriptions. A set of differential equations was sought, of reasonable chemical validity, that could embrace the observed oscillations, two-stage ignitions, cool-flames, and negative temperature coefficients. 

The system constants in Eqs. (1.6) and (1.7) are obtained by multiple linear regression analysis for a number of solute property determinations for solutes with known descriptors. The solutes used should be sufficient in number and variety to establish the statistical and chemical validity of the model [72-74]. In particular, there should be an absence of significant cross-correlation among the descriptors, clustering of either descriptor or dependent variable values should be avoided, and an exhaustive fit should be obtained. Table 1.4 illustrates part of a typical output. The overall correlation coefficient, standard error in the estimate, Fischer F-statistic, and the standard deviation in the individual system constants are used to judge whether the results are statistically sound. An exhaustive fit is obtained when small groups of solutes selected at random can be deleted from the model with minimal change in the system constants. 

The focus of this chapter is bulk pharmaceutical chemical validation. Aside from the history section, the information presented to this point would apply to most any type of process. That commonality with other older validation efforts is deliberate. Bulk pharmaceutical chemical validation is unique, only to the extent that BPCs are unique. The underlying maxims of success for validation (the knowledge and understanding of the scientific basis upon which the equipment or process is based) are universal. Mastery of the overall approach equips one to effectively employ those concepts in a variety of settings. Some knowledge of the key concerns in the production of BPCs is essential to understanding how the validation of their preparation should be carried out. 

Physical hazard of a chemical— A chemical validated as being or having one of the following characteristics combustible liquid, compressed gas, explosive, flannnable, organic peroxide, oxidizing qualities, pyrophoric, unstable, or water reactive. 

The connection table and bond table are used to assign the number of hydrogens to be attached to each atom and other chemical validity checks are carried out. 

Additionally, since our design strategy involves the transformation of one molecule into another it was necessary to develop a means to do this automatically if it were to be efficient. Performing the chemical transformations with a text editor incurs the risk of generating nonsense chemical structures. Thus for this purpose we needed to describe to a computer program how to transform the database molecules to the compounds suggested for synthesis in such a way that only chemically valid structures would be produced. 

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