Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists

Organic and Biomolecular Chemistry

Volumn 1, Issue 19, 2003, Pages 3353-3361

  McCluskey, Adam ^a   Keller, Paul A ^b   Morgan, Jody ^b   Garner, James ^a  

^a UNIVERSITY OF NEWCASTLE   (Australia)

^b UNIVERSITY OF WOLLONGONG   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG THERAPY; HORMONES; MOLECULAR WEIGHT; PROTEINS; SYNTHESIS (CHEMICAL);

REGIOCHEMISTRY;

BIOCHEMISTRY;

EID: 0142031003     PISSN: 14770520     EISSN: None     Source Type: Journal    
DOI: 10.1039/b305458f     Document Type: Article

References (26)

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26. The cost analysis of any pharmacophore is a statistical representation of the probability of the pharmacophore being a true representation of the data. This value is the difference (in bits) between the null cost (cost of generating a hypothesis where the error cost is high) and the total cost (actual cost of hypothesis generation) of the hypothesis generated. If the difference between the total cost and the null hypothesis cost is more than 60 bits, there is greater than 90% probability that the model is a true representation of the data. If the difference is 40-60 bits, there is a 7590% chance that it represents a true correlation of the data. When the difference becomes less than 40 bits, the probability of the hypothesis being a true representation rapidly falls below 50% and if the total - null cost difference is less than 20 bits there is little chance of it being accurate and the training set should be reconsidered. These analyses are the underpinning statistical validation of the visual output as represented in Fig. 2, and is the Catalyst programs' direct measure of the validity of a hypothesis generated. Therefore, when comparing similar pharmacophores (e.g. by refinement), it is the null - total cost difference that yields the direct statistical comparison of which is the better pharmacophore, where the greater the difference, the more accurate the model. The greater the difference between the null cost and the total cost the more statistically valid the hypothesis is, and the greater the probability of this model being a true representation of the data. Note, that an analysis such as this does not necessarily produce the lowest cost hypothesis as the best pharmacophore model. This refinement and analysis process was used for the all the pharmacophore models generated.