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The transport rate constant of a drug partitioned in a two-phase system from an aqueous to an organic phase (k1obs) and vice versa (k2obs) is a function of the partition coefficient P and of a solvent system-dependent parameter beta. Drug transport is shown to be independent of molecular structure for a number of arbitrary compounds.
At first sight, the QSAR issue might appear to be a mere pattern recognition problem; however, a purely "surface" approach to QSAR as a pattern recognition problem, not involving the profound plausibility of the solutions, has often been demonstrated to be devoid of scientific value and of predictive strength. The requirement for such a lateral validation should imply the recognition of the basic differences between the two terms of the QSAR issue: biology and chemistry. In particular, the difficulty to derive strong quantitative theories for the biological aspect of QSAR procedures should be taken into serious consideration. Within this conceptual framework, this paper examines the different families of mathematical models (classical regression, multivariate methods, neural networks) used in the QSAR research.
LC50-experiments have been conducted using guppies subjected to 72 industrial pollutants. The correlation of the LC50 with several expressions of the hydrophobicity of these chemicals has been studied. Calculated log Poct-values appeared to satisfy more than HPLC retention indices, solubility data or molecular connectivity indices. One QSAR, with log Poct as the only variable, gave good estimations of the toxicity of most of the tested compounds with log Poct less than 6. No LC50 could be determined for solutions of compounds with log Poct greater than 6.
Breast cancer resistance protein (BCRP) is a newly identified ABC transporter, which plays an important role in drug disposition and represents an additional mechanism for the development of MDR. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be BCRP inhibitors. The objective of the present study was to elucidate the SAR and derive a QSAR model for flavonoid-BCRP interaction. The EC(50) values for increasing mitoxantrone accumulation in MCF-7 MX100 cells for 25 flavonoids, from five flavonoid subclasses, were determined in this study or obtained from our previous publication [Zhang S, Yang X, Morris ME. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res 2004;21(7):1263-73], and ranged from 0.07+/-0.02 microM to 183+/-21.7 microM. We found that the presence of a 2,3-double bond in ring C, ring B attached at position 2, hydroxylation at position 5, lack of hydroxylation at position 3 and hydrophobic substitution at positions 6, 7, 8 or 4', are important structural properties important for potent flavonoid-BCRP interaction. These structural requirements are similar but not identical to those for potent flavonoid-NBD2 (P-glycoprotein) interaction, indicating that inhibition of BCRP by flavonoids may involve, in part, the binding of flavonoids with the NBD of BCRP. In addition, a QSAR model consisting three structural descriptors was constructed, and both internally and externally validated, suggesting the model could be used to quantitatively predict BCRP inhibition activity of flavonoids. These findings should be useful for predicting BCRP inhibition activity of other untested flavonoids and for guiding the synthesis of potent BCRP inhibitors for potential clinical application.
A new series of novel piperazine and non-piperazine derivatives of 2, 4-diamino-6,7-dimethoxyquinazoline was synthesized and evaluated for binding affinity toward alpha1-adrenergic and other G-protein-coupled aminergic receptors. The alpha1-adrenoceptor (AR) subtype selectivity was also investigated for the most interesting compounds. Only compound 16 showed moderate selectivity toward the alpha1b-AR subtype. Selected compounds were tested in vivo in a dog model indicating activity on blood pressure and on the lower urinary tract. Compound 10 showed in vivo potency close to that of prazosin. Powerful interpretative and predictive theoretical QSAR models have been obtained. The theoretical descriptors employed in the rationalization of the alpha1-adrenergic binding affinity depict the key features for receptor binding which can be summarized in an electrostatic interaction between the protonated amine function and a primary nucleophilic site of the receptor, complemented by short-range attractive (polar and dispersive) and repulsive (steric) intermolecular interactions. Moreover, on predictive grounds, the ad hoc derived size and shape QSAR model developed in a previous paper (Rastelli, G.; et al. J. Mol. Struct. 1991, 251, 307-318) proved to be successful in predicting nanomolar alpha1-adrenergic binding affinity for compound 28.
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Cytotoxicities of 93 quinazoline derivatives against HeLa cells have been determined as the isoeffective concentrations inhibiting, after a single dose, the protein synthesis to 50% of the control amount after 48 h incubation. The dependence of cytotoxicity on hydrophobicity of the studied derivatives has been described using a previously published model-based approach. The studied derivatives are classified into nine classes each forming a smooth hydrophobicity-cytotoxicity curve. Owing to the acceptable agreement between the model and the data it can be inferred that: (1) the compounds except two derivatives bind to the receptors with approximately the same affinity; (2) the criterion for the classification is the different rate of metabolism. The results represent a basis for a rational development of more potent quinazoline derivatives.
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Active and Withdrawn syndromes in schizophrenia have been associated with different patterns of lateral asymmetry: higher left than right hemisphere activity in the Active syndrome and the opposite pattern in the Withdrawn syndrome. Here validation was explored with a power spectral analysis of the visual evoked potential recorded to flashes of five different intensities from primary sensory occipital cortex (O1, O2) and from temporal (T3, T4) cortex. Unmedicated schizophrenic patients were categorised as Active or Withdrawn syndrome by clinical ratings. Pattern of lateral asymmetry of electrodermal orienting responses was recorded and was found to be as predicted: larger on the left than right hand in the Active syndrome with the opposite pattern in the Withdrawn syndrome. Normal controls were also examined. At occipital placements the main results were in beta (18-22 Hz) in which (1), syndromes showed opposite asymmetry patterns consistent with predictions: higher power on the left in the Active syndrome and on the right in the Withdrawn syndrome and (2), there was an absence of normal stimulus intensity/beta power relations in the Withdrawn syndrome. The Active syndrome showed abnormal relations at the temporal location, reflected in high alpha activity (10-14 Hz), together with an abnormal asymmetry in 2-6 Hz activity in the direction of more slow wave activity in the right hemisphere, a lateral asymmetry consistent with the model. When compared with the controls the Withdrawn syndrome was dysfunctional at lower, sensory cortex, levels of processing while the Active syndrome was dysfunctional at higher, temporal cortex, stages of processing. Schizophrenic patients as a group were characterised by abnormal desynchronisation of left temporal activity.
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