Estimation of reliability of predictions and model applicability domain evaluation in the analysis of acute toxicity (LD50).

This study presents a new type of acute toxicity (LD(50)) prediction that enables automated assessment of the reliability of predictions (which is synonymous with the assessment of the Model Applicability Domain as defined by the Organization for Economic Cooperation and Development). Analysis involved nearly 75,000 compounds from six animal systems (acute rat toxicity after oral and intraperitoneal administration; acute mouse toxicity after oral, intraperitoneal, intravenous, and subcutaneous administration). Fragmental Partial Least Squares (PLS) with 100 bootstraps yielded baseline predictions that were automatically corrected for non-linear effects in local chemical spaces--a combination called Global, Adjusted Locally According to Similarity (GALAS) modelling methodology. Each prediction obtained in this manner is provided with a reliability index value that depends on both compound's similarity to the training set (that accounts for similar trends in LD(50) variations within multiple bootstraps) and consistency of experimental results with regard to the baseline model in the local chemical environment. The actual performance of the Reliability Index (RI) was proven by its good (and uniform) correlations with Root Mean Square Error (RMSE) in all validation sets, thus providing quantitative assessment of the Model Applicability Domain. The obtained models can be used for compound screening in the early stages of drug development and prioritization for experimental in vitro testing or later in vivo animal acute toxicity studies.

Fragmental methods in the analysis of biological activities of diverse compound sets.

The current mini-review explains how fragmental methods (FMs) can be used in the analysis and prediction of physicochemical properties and biological activities. The considered properties include log P, solubility, pK(a), intestinal permeability, P-gp substrate specificity and toxicity. The focus will be a description of a "mechanistic" approach, which implies a gradual reduction of alternative explanations for any property or activity. This means a flexible construction of fragmental parameters using large amounts of experimental data. Since biological activities involve multiple (unknown) target macromolecules with multiple binding modes, a stepwise classification (C-SAR) analysis is most useful. It involves the following procedures: (i). construction of physicochemical profiles using parameters that can be reliably predicted, (ii). identification of reactive functional groups and the largest active skeletons, (iii). generalization of these groups and skeletons in terms of "site-specific physicochemical profiling". This entails a dynamic construction of 2D pharmacophores that can be converted into 3D models.

Time trends in incidence of cervical cancer in Lithuania from 1983 to 1997.

This report examines time trends in both age-specific and age-standardized cervical cancer (ICD9-180) incidence rates among Lithuanian women. The study covers the period from 1983 to 1997. In case of the age-specific rates Poisson regression revealed the controversial results for the different age groups. The incidence rates increased (beta > 0) for the women below 50 years and decreased (beta < 0) for the women above 50 years. The average annual percentage changes were estimated using the age-drift model. In the age groups from 30 to 49 years old the incidence rate increased by 3.3% per year with the 95% confidence interval (CI) being 2.2-4.4. In the age groups from 50 to 69 years old the incidence rate decreased by 2.9% (95% CI: 1.9-3.8). In case of the age-standardized rates during the last few years some increase was observed, although no strict conclusions could be drawn. This observation together with the results of the age-specific rate studies predicts that in the near future the age-standardized rate will start growing.

Penicillin acylase-catalyzed protection and deprotection of amino groups as a promising approach in enzymatic peptide synthesis.

Penicillin acylase from E. coli is able to catalyze both the introduction and the removal of the phenylacetyl group. We have established that phenylacetyl derivatives of amino acids and peptides can be used in protease-catalyzed peptide synthesis. Here the synthesis of leucine-enkephalin using enzymes for N-terminal amino group protection, peptide bond formation and deprotection is described.

Penicillin acylase-catalyzed acyl group transfer to amino acids, their esters and peptides: a kinetic study.

Kinetics of penicillin acylase-catalyzed acyl group transfer to amino acids, their esters and peptides have been analyzed. The synthesized product accumulation curves have clearly expressed a maximum. Amino acids with non-branched side chain alkyl radicals were demonstrated to be effective nucleophiles, with glycine, L-phenylalanine and L-phenylglycine being the best. D-amino acids were shown to possess much lower reactivity. Practically for all L-amino acids and peptides tested, the yield of their N-phenylacetyl derivatives in the course of penicillin acylase-catalyzed acyl group transfer reactions was found to be more than 50%. Optimization of such enzymatic synthesis required to increase its potential on the preparative scale.