20 research outputs found
Destabilizers of the thymidylate synthase homodimer accelerate its proteasomal degradation and inhibit cancer growth
A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields
QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability
We collected 1173 hERG patch clamp (PC) data (IC<sub>50</sub>)
from the literature to derive twelve classification models for hERG
inhibition, covering a large variety of chemical descriptors and classification
algorithms. Models were generated using 545 molecules and validated
through 258 external molecules tested in PC experiments. We also evaluated
the suitability of the best models to predict the activity of 26 proprietary
compounds tested in radioligand binding displacement (RBD). Results
proved the necessity to use multiple validation sets for a true estimation
of model accuracy and demonstrated that using various descriptors
and algorithms improves the performance of ligand-based models. Intriguingly,
one of the most accurate models uncovered an unexpected link between
extent of metabolism and hERG liability. This hypothesis was fairly
reinforced by using the Biopharmaceutics Drug Disposition Classification
System (BDDCS) that recognized 94% of the hERG inhibitors as extensively
metabolized <i>in vivo</i>. Data mining suggested that high
Torsades de Pointes (TdP) risk results from an interplay of hERG inhibition,
extent of metabolism, active transport, and possibly solubility. Overall,
these new findings might improve both the decision making skills of
pharmaceutical scientists to mitigate hERG liability during the drug
discovery process and the TdP risk assessment during drug development
QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability
We collected 1173 hERG patch clamp (PC) data (IC<sub>50</sub>)
from the literature to derive twelve classification models for hERG
inhibition, covering a large variety of chemical descriptors and classification
algorithms. Models were generated using 545 molecules and validated
through 258 external molecules tested in PC experiments. We also evaluated
the suitability of the best models to predict the activity of 26 proprietary
compounds tested in radioligand binding displacement (RBD). Results
proved the necessity to use multiple validation sets for a true estimation
of model accuracy and demonstrated that using various descriptors
and algorithms improves the performance of ligand-based models. Intriguingly,
one of the most accurate models uncovered an unexpected link between
extent of metabolism and hERG liability. This hypothesis was fairly
reinforced by using the Biopharmaceutics Drug Disposition Classification
System (BDDCS) that recognized 94% of the hERG inhibitors as extensively
metabolized <i>in vivo</i>. Data mining suggested that high
Torsades de Pointes (TdP) risk results from an interplay of hERG inhibition,
extent of metabolism, active transport, and possibly solubility. Overall,
these new findings might improve both the decision making skills of
pharmaceutical scientists to mitigate hERG liability during the drug
discovery process and the TdP risk assessment during drug development
From 6-aminoquinolone antibacterials to 6-amino-7- thiopyranopyridinylquinolone ethyl esters as inhibitors of staphylococcus aureus multidrug efflux pumps
The thiopyranopyridine moiety was synthesized as a new heterocyclic base to be inserted at the C-7 position of selected quinolone nuclei followed by a determination of antibacterial activity against strains of Staphylococcus aureus. Selected thiopyranopyridinylquinolones showed significant antimicrobial activity, including strains having mutations in gyrA and grlA as well as other strains overexpressing the NorA multidrug (MDR) efflux pump. Most derivatives did not appear to be NorA substrates. The effect of the thiopyranopyridinyl substituent on making these quinolones poor substrates for NorA was investigated further. Several quinolone ester intermediates, devoid of any intrinsic antibacterial activity, were tested for their abilities to inhibit the activities of NorA (MFS family) and MepA (MATE family) S. aureus MDR efflux pumps. Selected quinolone esters were capable of inhibiting both MDR pumps more efficiently than the reference compound reserpine. Moreover, they also were able to restore, and even enhance, the activity of ciprofloxacin toward some genetically modified resistant S. aureus strains. © 2010 American Chemical Society
Correction to From 6-Aminoquinolone Antibacterials to 6-Amino-7-thiopyranopyridinylquinolone Ethyl Esters as Inhibitors of Staphylococcus aureus
Ligand-based virtual screening and ADME-tox guided approach to identify triazolo-quinoxalines as folate cycle inhibitors
In the process of drug discovery the lead-identification phase may be critical due to the likely poor safety profile of the candidates, causing the delay or even the abandonment of a certain project. Nowadays, combining molecular modeling and in vivo cellular evaluation can help to identify compounds with an enhanced safety profile. Previously, two quinoxalines have been identified as inhibitors of the folate-dependent proteins belonging to the thymidylate synthase cycle. Unfortunately, cytotoxic activity against a panel of cisplatin(cDDP)-sensitive ovarian carcinoma cell lines and their resistant counterparts was coupled with toxicity to non-tumorigenic Vero cells. Here we describe the application of a ligand-based virtual screening, and several [1,2,4]triazolo[4,3-a]quinoxalines were optimized to improve their ADME-tox profile. The resulting 4-(trifluoromethyl)-1-p-tolyl-[1,2,4]triazolo[4,3-a]quinoxaline (24), which interferes intracellularly with DHFR and TS reducing the protein levels like 5-FU, but without inducing TS ternary complex formation, was 2-times less toxic in vitro than cisplatin and 5-FU
Absolute configuration and biological profile of two thiazinooxadiazol-3-ones with L-type calcium channel activity: a study of the structural effects
In the framework of our interest in racemic thiazinooxadiazol-3-ones we determined the absolute configuration and the biological activity as L-type calcium channel blockers of two compounds that differ in the length of the acetal chain, which could affect the pharmacological profile. We observed an
interesting inversion of the stereoselectivity, with the activity residing on the R-form for a short chain compound (n = 1) and on the S-form for a long chain one (n = 12). The length of the linear acetal chain appears to be able to invert the stereoselectivity of such a class of compounds, and in silico simulations suggested that this different behaviour might be explained by different hydrophilic and hydrophobic
interactions with the binding site
Stereoselective behavior of the functional diltiazem analogue 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a new L-type calcium channel blocker
We studied the stereoselective behavior of 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a recently described blocker of cardiovascular L-type calcium channels that binds to the diltiazem site. Given the stereocenter at C-2 of the pyrrolidine ring, the two enantiomers were separated by chiral HPLC and, using VCD in conjunction with DFT calculations of chiroptical properties, the absolute configuration was assigned as R-(þ)/S-(-). For both forms, functional, electrophysiological, and binding properties were studied and the three-dimensional superimpositions of the two enantiomers over diltiazem were obtained in silico. The significant differences observed for the two enantiomers well agreed with the experimental data, and molecular regions were hypothesized as responsible for the cardiac stereoselectivity and vascular stereospecificity