Malgorzata N. Drwal

Learn More
Animal trials are currently the major method for determining the possible toxic effects of drug candidates and cosmetics. In silico prediction methods represent an alternative approach and aim to rationalize the preclinical drug development, thus enabling the reduction of the associated time, costs and animal experiments. Here, we present ProTox, a web(More)
The combination of ligand- and structure-based molecular modelling methods has become a common approach in virtual screening. This review describes different strategies for integration of ligand- and structure-based methods which can be divided into sequential, parallel or hybrid approaches. Although no thorough performance comparisons between combined(More)
DNA topoisomerases are enzymes responsible for the relaxation of DNA torsional strain, as well as for the untangling of DNA duplexes after replication, and are important cancer drug targets. One class of topoisomerase inhibitors, "poisons", binds to the transient enzyme-DNA complex which occurs during the mechanism of action, and inhibits the religation of(More)
Post-marketing drug withdrawals can be associated with various events, ranging from safety issues such as reported deaths or severe side-effects, to a multitude of non-safety problems including lack of efficacy, manufacturing, regulatory or business issues. During the last century, the majority of drugs voluntarily withdrawn from the market or prohibited by(More)
Synaptic glycine receptors (GlyRs) are hetero-pentameric chloride channels composed of α and β subunits, which are activated by agonist binding at subunit interfaces. To examine the pharmacological properties of each potential agonist-binding site, we substituted residues of the GlyR α(1) subunit by the corresponding residues of the β subunit, as deduced(More)
DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1-DNA covalent complex. This complex can be trapped by a group of(More)
Tropeines are bidirectional modulators of native and recombinant glycine receptors (GlyRs) and promising leads for the development of novel modulatory agents. Tropisetron potentiates and inhibits agonist-triggered GlyR currents at femto- to nanomolar and micromolar concentrations respectively. Here, the potentiating and inhibitory effects of another(More)
To assess the toxicity of new chemicals and drugs, regulatory agencies require in vivo testing for many toxic endpoints, resulting in millions of animal experiments conducted each year. However, following the Replace, Reduce, Refine (3R) principle, the development and optimization of alternative methods, in particular in silico methods, has been put into(More)
Purely structure-based pharmacophores (SBPs) are an alternative method to ligand-based approaches and have the advantage of describing the entire interaction capability of a binding pocket. Here, we present the development of SBPs for topoisomerase I, an anticancer target with an unusual ligand binding pocket consisting of protein and DNA atoms. Different(More)
Promiscuity is an interesting concept in fragment-based drug design as fragments with low specificity can be advantageous for finding many screening hits. We present a PDB-wide analysis of multi-target fragments and their binding mode conservation. Focussing on multi-target fragments, we found that the majority shows non-conserved binding modes, even if(More)