JChem: Java applets and modules supporting chemical database handling from web browsers

A Java based development tool for building portable chemical information systems is presented. The system contains applets for constructing web-based interfaces and classes that add structure handling to relational databases. Custom applications built with JChem can combine SQL and structural queries.

Prediction of distribution coefficients from structure. Comparison of calculated and experimental data for various drugs.

The efficiency of the program PrologD to predict distribution coefficients (D) at any pH and pairing ion concentration has been tested using experimental logD values for various drugs measured under standard conditions of buffers and ionic strength. Clonidine derivatives, fluoroquinolones and beta-blockers were included as particular pharmacological classes within the testing data set. Calculations were performed using the three logP estimation options implemented in the program. PrologD proved to be very efficient and can be of great advantage in drug research. Prediction patterns and correlations between experimental and calculated data indicate acceptable results for more than 80% of the data. In addition, comparable studies using the different options permitted suggestions for the more suitable logP estimation method in respect of the particular classes of compounds.

Metrics comparing simulated early concentration profiles for the determination of bioequivalence.

PURPOSE: To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. METHODS: Two-period crossover trials were simulated with increasing assumed ratio of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC(AUCP), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I L/H), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (MLOG). For comparison, also properties of CMAX and an ideally evaluated measure (Id) were determined. RESULTS: MLOG showed generally the highest statistical power and KS, and also the largest SE, closely followed by I L/H. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than CMAX. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. CONCLUSIONS: The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. MLOG had the highest statistical power, closely followed by I L/H and then by partial AUC.

The duration of measuring partial AUCs for the assessment of bioequivalence.

PURPOSE: To determine favourable sampling conditions for assessing bioequivalence by the comparison of partial AUCs in the early phase of concentration-time profiles. METHODS: Two-period crossover trials were simulated. They assumed a wide range of the ratios of absorption rate constants of the test (T) and reference (R) formulations (kaT/kaR). Averages and standard deviations of the corresponding ratios of simulated partial AUCs (AUCpT/AUCpR) were determined together with the statistical power of assessing bioequivalence, i.e., the percentage of simulated trials in which bioequivalence was declared. RESULTS: The power for stating bioequivalence was high when AUCp was recorded until the earlier rather than the later of two peaks in each subject. Similarly, power was comparatively high when AUCp was measured until the time of the reference peak instead of multiples of this time. Power was high also when AUCp was determined until the fixed true, population mean time of the reference formulation instead of multiples of this time. The pattern for the kinetic sensitivity parallelled that found for the power, while the standard deviations changed generally in the opposite direction. CONCLUSIONS: The effectiveness (power) of evaluating bioequivalence in the early phase of concentration-time profiles by partial AUCs generally decreases when the duration for measuring the metric is extended. Among the investigated designs, determination of partial AUCs until the earlier of two peaks in each subject is the most powerful.

Model-independent estimation of lag times with first-order absorption and disposition.

The effectiveness of five model-independent procedures for the estimation of lag times (Tlag) was evaluated. Two new methods utilize early concentrations which are weighted by a term exponential in time. They estimate Tlag by weighted linear regression. One of these approaches evaluates also the time when maximum concentration is reached (Tmax). In addition, three older, empirically used procedures are considered. Two methods apply either the first two or three quantifiable concentrations and estimate the lag time by linear regression. Finally, the last unquantifiable concentration is often used as a measure of lag time. Simulations demonstrated that this procedure had large bias and generally high standard deviation. In contrast, the new methods showed small variation and negligible bias. The procedures applying linear regression had intermediate characteristics. Lag times were evaluated effectively by an average of two observations between Tlag and Tmax.

Prediction of distribution coefficient from structure. 2. Validation of Prolog D, an expert system.

Prolog D is a program that formalizes, in a controllable and reproducible manner, an algorithm developed to predict distribution coefficients of ionizable compounds at a given pH and varying counterion concentrations. Its predictive power has been evaluated with experimental log D values measured under standard conditions of buffers and ionic strength. Calculations were performed with the three different options for the estimation of partition coefficients (log P) implemented in the program. Considering the diversity of test compounds as well as the present state of the art in log P and pKa predictions, Prolog D proved to be very efficient and can be used as a tool to provide lipophilicity data. Prediction patterns and correlations with the observed data are of almost equal quality for all options, permitting acceptable results for 80% of the data.

Prediction of distribution coefficient from structure. 1. Estimation method.

A method has been developed for the estimation of the distribution coefficient (D), which considers the microspecies of a compound. D is calculated from the microscopic dissociation constants (microconstants), the partition coefficients of the microspecies, and the counterion concentration. A general equation for the calculation of D at a given pH is presented. The microconstants are calculated from the structure using Hammett and Taft equations. The partition coefficients of the ionic microspecies are predicted by empirical equations using the dissociation constants and the partition coefficient of the uncharged species, which are estimated from the structure by a Linear Free Energy Relationship method. The algorithm is implemented in a program module called PrologD.

In vitro antiviral activities of myristic acid analogs against human immunodeficiency and hepatitis B viruses.

A group of myristic acid analogs, designed as alternative substrates for N-myristoyltransferase (NMT), were evaluated against human immunodeficiency virus (HIV), hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) in vitro. Antiviral potency was increased when S or O was substituted for -CH2- in myristic acid and selectivity was affected by the presence and position of the heteroatoms and phenyl groups. A correlation was established among anti-HIV activity, Log P and Log D7.4 and between anti-HIV activity and carbonyl-heteroatom interatomic distances in the myristoyl analogs. 12-Thioethyldodecanoic acid 6 was moderately active (EC50 = 9.37 microM) against HIV-infected T4-lymphocytes (CEM-SS cell line), and it exhibited in vitro activity (EC50 = 17.8 microM) against HBV-producing 2.2.15 cell cultures derived from a human hepatoblastoma cell line (Hep G2). 12-Methoxydodecanoic acid 1 exhibited in vitro activity (EC50 = 20-30 microM) against hepatitis B in the HBV DNA-transfected 2.2.15 cell line. At a concentration of 10 microg/ml, none of the fatty acids significantly inhibited the replication of DHBV in infected hepatocytes.

Synthesis and antifungal activities of myristic acid analogs.

Myristic acid analogs that are putative inhibitors of N-myristoyl-transferase were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans) and filamentous fungi (Aspergillus niger). Several (+/-)-2-halotetradecanoic acids including (+/-)-2-bromotetradecanoic acid (14c) exhibited potent activity against C. albicans (MIC = 39 microM), C. neoformans (MIC = 20 microM), S. cerevisiae (MIC = 10 microM), and A. niger (MIC < 42 microM) in RPMI 1640 media. Improved synthetic methods have been developed for the synthesis of 12-fluorododecanoic acid (12a) and 12-chlorododecanoic acid (12c). Three novel fatty acids, 12-chloro-4-oxadodecanoic acid (8a), 12-phenoxydodecanoic acid (12i), and 11-(4-iodophenoxy)-undecanoic acid (13d) were also synthesized and tested.