Biomedical subjects

F Darvas

Publications and source records attributed to F Darvas.

21 records · Page 2Linked to original sources

PubMedDate not supplied

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.

Animals↗

PubMedDate not supplied

UV-triggered main-component fraction collection method and its application for high-throughput chromatographic purification of combinatorial libraries.

A maximum-seeking, algorithm-driven fraction collection method was developed to support high-throughput chromatographic purification, which provides new possibilities for off-line high-performance liquid chromatography mass spectroscopy (HPLC/MS) quality control experiments. The method is based on manipulation of a six-port valve that is installed downstream from the UV detector and equipped with a fraction collector loop. The detector signal is monitored by a programmable microcontroller that controls the state of the fraction collector valve. After detecting a chromatographic peak, the appropriate fraction is stored in the collector loop. The height of the next peak is compared to the previous one (using a maximum-seeking algorithm) and, depending on the result, the collected fraction is or is not exchanged with the new one. At the end of the run, the stored UV main component is pumped into the external fraction vial. This configuration was used for chromatographic purification of large compound libraries (the results of the purification of 5324 compounds are reported here), as well as for high-throughput off-line HPLC quality control experiments, where the collected main component fractions of an analytical-scale separation were subjected to further mass spectrometric molecular weight verification.

Algorithms↗

PubMedDate not supplied

Diversity measures for enhancing ADME admissibility of combinatorial libraries.

For general screening libraries, structural diversity descriptors and drug-likeness indicators still do not guarantee the in vivo bioavailability for the candidates, which is considered a major bottleneck in drug development. Early prediction of pharmacokinetics (log P, log D), metabolism, and toxicity makes it possible to deal with ADME (adsorption, distribution, metabolism, excretion) related diversity as an extension to the classical diversity concepts. It opens several new possibilities for optimization of a discovery library before doing any experimental screening. This new diversity concept is demonstrated on a subset of MeDiverse, which is a diverse collection of pharmacologically relevant compounds selected from our in-house library. From consideration of the ADME interface in living systems, virtual secondary libraries of metabolites and retrometabolites (prodrugs) can be generated. These additional libraries readily enhance both the structural and ADME related diversity. This new opportunity in library design can substantially improve the success rate for in vivo lead generation from in vitro hits.

Biological Assay↗