To better evaluate, in the context of QSAR studies, new validation techniques such as bootstrapping and crossvalidation and the new analytic technique of partial least squares (PLS), seventeen QSAR results taken from nine recent publications were reexamined using these techniques. The results indicate that bootstrapping and crossvalidation are more powerful indicators of possible chance correlation than are the classical tests based on assumed normal independent distribution of variables. Although PLS will not detect all correlations existing within a set of data, its conservative behavior is particularly valuable when the candidate physicochemical descriptors are numerous and non-orthogonal.

Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR Studies

Molecular hydrophobicity (lipophilicity), usually quantified as log P (the logarithm of 1-octanol/water partition coefficient), is an important molecular characteristic in drug discovery. ALOGP and CLOGP are two of the most widely used methods for the estimation of log P. This work describes an extensive reparametrization of the atomic log P values and a detailed comparison of the performance of ALOGP and CLOGP methods on the Pomona Medchem database. Only the “star list” compounds having precisely measured log P values were used in this analysis. While the overall results with both methods are similar, analysis shows that the CLOGP method is better for very small molecules in the range of 1−20 atoms. The two methods are almost comparable in the range of 21−45 atoms, while the ALOGP method has better accuracy for molecules with more than 45 atoms. Although the rms deviation and the correlation coefficient for CLOGP predictions were marginally better than those for corresponding ALOGP predictions, the latte...

Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods

Determination of hydrophobic parameters by reversed-phase liquid chromatography: theory, experimental techniques, and application in studies on quantitative structure-activity relationships

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.2600760902

Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.2600620102

Lipophilic Character and Biological Activity of Drugs II: The Parabolic Case

The mutagenic activity of a series of nitroimidazo (2,1-b) thiazoles was determined in Salmonella typhimurium TA-100 strain by means of the Ames test. A multiple regression analysis showed a highly significant parabolic relationship between mutagenic activity and the Rm values as an expression of the lipophilic character of molecules. The lipophilic character should be important in determining an optimal cell permeation. However when the lipophilic character was expressed by means of the Σπ values the equation was much less satisfactory. This could be due to the fact that the Rm values of nitroheterocyclic compounds actually represent a measure both of lipophilic and polar character.

Structure-Activity Relationshipof Nitroimidazo (2,1-b) Thiazoles in the Salmonella Mutagenicity Assay

Urinary excretion of mutagenic forms of metronidazole and nine related compounds as detected by HPLC

The relationship between physicochemical parameters and biliary excretion of nitroimidazoles was investigated. The unmetabolized form of each drug was detected in the bile by means of a UV procedure. A highly significant reversed parabolic relationship was shown between the Rm values and the biliary excretion of the test compounds. In other words, the compounds closer to the optimal Rm value are excreted less than those characterized by higher or lower Rm values. Since the Rm values seem to account for both the lipophilic and polar character of nitroimidazoles, the reversed parabola could be due to plasma protein binding and/or some protein binding within the hepatocyte. In fact, both the lipophilic and polar character seem to play an important role in protein binding of chemicals.

The influence of physicochemical parameters on the biliary excretion of a series of nitroimidazoles.

Lipophilic character of cardiac glycosides

Un metodo cromatografico su strato sottile a fasi invertite ha permesso di ottenere valori Rm altamente correlati con il legame con l'albumina in due serie di corticosteroidi e androgeni.

/pdf/relationship-between-r-m-values-and-protein-binding-of-19w4koabdu.pdf

A.M. Barbaro

Papers

Structure-Activity Relationshipof Nitroimidazo (2,1-b) Thiazoles in the Salmonella Mutagenicity Assay

Urinary excretion of mutagenic forms of metronidazole and nine related compounds as detected by HPLC

The influence of physicochemical parameters on the biliary excretion of a series of nitroimidazoles.

Lipophilic character of cardiac glycosides

Relationship between R m values and protein binding of corticosteroids and androgens.