Drug efficiency index

Valko, K., Chiarparin, E., Nunhuck, S., and Montanari, D. (2012) In vitro measurement of drug efficiency index to aid early lead optimization. Journal of Pharmaceutical Sciences, 101, 4155-4169. 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

The E-state indices may define chemical spaces that are relevant in similarity/ diversity search in chemical databases. This similarity search is based on atom-type E-state indices computed for the query molecule [55]. Each E-state index is converted to a z score, Z =(% -p )/0 , where is the ith E-state atomic index, p is its mean and O is its standard deviation in the entire database. The similarity was computed with the EucHdean distance and with the cosine index and the database used was the Pomona MedChem database, which contains 21000 chemicals. Tests performed for the antiinflamatory drug prednisone and the antimalarial dmg mefloquine as query molecules demonstrated that the chemicals space defined by E-state indices is efficient in identifying similar compounds from drug and drug-tike databases. 

The partitioning of the activated inhibitor between direct covalent inactivation of the enzyme and release into solution is an important issue for mechanism-based inactivators. The partition ratio is of value as a quantitative measure of inactivation efficiency, as described above. This value is also important in assessing the suitability of a compound as a drug for clinical use. If the partition ratio is high, this means that a significant proportion of the activated inhibitor molecules is not sequestered as a covalent adduct with the target enzyme but instead is released into solution. Once released, the compound can diffuse away to covalently modify other proteins within the cell, tissue, or systemic circulation. This could then lead to the same types of potential clinical liabilities that were discussed earlier in this chapter in the context of affinity labels, and would therefore erode the potential therapeutic index for such a compound. 

This method of analysis relies on the same chemical principles as the determination by TLC, except that the efficiency (and the cost) of the technique has increased greatly. Instead of the R value, the retention time of the drug is measured and related to P by equations similar to equation (2.5) for TLC. The retention time, as its name suggests, is the time taken for the sample to elute from the HPLC column. The major drawback with using this technique to determine P is detecting the drug if it does not possess a chromophore, when a UV detector cannot be used. In cases like this, use must be made of an HPLC system connected to a refractive index (RI) detector or an electrochemical detector (ECD). 

Bibliographic Retrieval Services (BRS) The Bibliographic Retrieval Services, Inc. of Scotia, New York also offer efficient access to several data bases that are relevant to chemical industry needs. BRS offers an on-line version of Chemical Abstracts CA search under the file label CHEM. Often a CHEM search can be supplemental with other BRS data bases. One can use the CROS file, which provides an index to all data bases on-line at BRS. BRS data bases include NTIS, Science SCISEARCH Citation Index, the Smithsonian Information Exchange (SMIE), and BIOSIS Previews. All are described in the previous section. A few of the MEDLARS data bases are available from BRS, as well as a data base called Pharmaceutical News Index that covers drug industry news. 

It has been well-defined that the efficiency of anitneoplastic drugs may be characterized by their inherent log cell-kill index. In other words, the negative log of the fraction of the cancerous tumor cell population which essentially survives a single-course of treatment. 

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