Discovery of Novel, Potent, and Specific Cell-Death Inducers in the Jurkat Acute Lymphoblastic Leukemia Cell Line.

The limited clinical efficacy of many cancer therapeutics has initiated intense research efforts toward the discovery of novel chemical entities in this field. In this study, 31 hit candidates were selected from nearly 800,000 database compounds in a ligand-based virtual screening campaign. In turn, three of these hits were found to have (sub)micromolar potencies in proliferation assays with the Jurkat acute lymphatic leukemic cell line.

Virtual fragment screening: discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints.

Virtual fragment screening (VFS) is a promising new method that uses computer models to identify small, fragment-like biologically active molecules as useful starting points for fragment-based drug discovery (FBDD). Training sets of true active and inactive fragment-like molecules to construct and validate target customized VFS methods are however lacking. We have for the first time explored the possibilities and challenges of VFS using molecular fingerprints derived from a unique set of fragment affinity data for the histamine H(3) receptor (H(3)R), a pharmaceutically relevant G protein-coupled receptor (GPCR).

Large, chemically diverse dataset of logP measurements for benchmarking studies.

Lipophilicity is a crucial parameter in drug development since it impacts both ADME properties and target affinity of drug candidates. In early drug discovery stage, accurate tools for logP prediction are highly desired. Many calculation methods were developed to aid pharmaceutical scientists in drug research; however almost all suffer from insufficient accuracy and variation of performance in several regions of the chemical space associated with new chemical entities.

Ligand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A(1), A (2A), A (2B), and A (3) receptor antagonists.

FLAP fingerprints are applied in the ligand-, structure- and pharmacophore-based mode in a case study on antagonists of all four adenosine receptor (AR) subtypes. Structurally diverse antagonist collections with respect to the different ARs were constructed by including binding data to human species only. FLAP models well discriminate "active" (=highly potent) from "inactive" (=weakly potent) AR antagonists, as indicated by enrichment curves, numbers of false positives, and AUC values.

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 (IC50) 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).

IAP antagonists: promising candidates for cancer therapy.

A promising strategy in cancer therapy aims to promote apoptosis in cancer cells. Targeting inhibitor of apoptosis proteins (IAPs) with small-molecule inhibitors has attracted increasing interest in triggering cancer cell death. It is considered to have great potential for cancer drug discovery because IAPs block apoptosis at the core of the apoptotic machinery and are aberrantly expressed in various tumors.

Large-scale evaluation of log P predictors: local corrections may compensate insufficient accuracy and need of experimentally testing every other compound.

A large variety of log P calculation methods failed to produce sufficient accuracy in log P prediction for two in-house datasets of more than 96000 compounds contrary to their significantly better performances on public datasets. The minimum Root Mean Squared Error (RMSE) of 1.02 and 0.

The pre-clinical assessment of rapamycin-eluting, durable polymer-free stent coating concepts.

All four currently FDA-approved drug-eluting stents (DESs) contain a durable polymeric coating which can negatively impact vascular healing processes and eventually lead to adverse cardiac events. Aim of this study was the pre-clinical assessment of two novel rapamycin-eluting stent (RES) coating technologies that abstain from use of a durable polymer. Two distinctive RES coating technologies were evaluated in vitro and in the porcine coronary artery stent model.

Calculation of molecular lipophilicity: State-of-the-art and comparison of log P methods on more than 96,000 compounds.

We first review the state-of-the-art in development of log P prediction approaches falling in two major categories: substructure-based and property-based methods. Then, we compare the predictive power of representative methods for one public (N = 266) and two in house datasets from Nycomed (N = 882) and Pfizer (N = 95809). A total of 30 and 18 methods were tested for public and industrial datasets, respectively.

Novel TOPP descriptors in 3D-QSAR analysis of apoptosis inducing 4-aryl-4H-chromenes: comparison versus other 2D- and 3D-descriptors.

Novel 3D-descriptors using Triplets Of Pharmacophoric Points (TOPP) were evaluated in QSAR-studies on 80 apoptosis-inducing 4-aryl-4H-chromenes. A predictive QSAR model was obtained using PLS, confirmed by means of internal and external validations. Performance of the TOPP approach was compared with that of other 2D- and 3D-descriptors; statistical analysis indicates that TOPP descriptors perform best.

Virtual screening for novel openers of pancreatic K(ATP) channels.

Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening.

Structure-activity relationships of K(ATP) channel openers.

Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs) e.

Second-generation K(ATP) channel openers.

This review discusses structural aspects of second-generation K(ATP) channel openers (KCOs), which exhibit improved tissue-selectivity. Their therapeutic profile is debated with main focus on cardiac ischemia, asthma, and urinary incontinence.

Binding studies and GRIND/ALMOND-based 3D QSAR analysis of benzothiazine type K(ATP)-channel openers.

For seventeen 1,4-benzothiazine potassium channel openers, we performed binding studies in rat aortic smooth muscle cells and cardiomyocytes, compared their binding affinities with published relaxation data, and derived 3D-QSAR models using GRIND/ALMOND descriptors. Binding affinities in smooth muscle cells range from a pK(D) of 4.76 for compound 3e to 9.

Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide AT1, AT2, and AT1/AT2 angiotensin II receptor antagonists.

About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II receptor subtype 2) receptor subtypes.

log P estimation of 1,2-dithiole-3-thiones and 1,2-dithiole-3-ones: a comparison of experimental and calculative approaches.

Purpose: To estimate experimental log P values of formerly described 5-formyl- and 5-acyl-dithiole-3-thiones (DTT) and -dithiole-3-ones (DTO) and to check the validity of five log P calculation programs via experimental log P for a database of 68 DTT and DTO.

Methods: Experimental log P values were measured by means of octanol/water partitioning; for determining solute concentrations in water, RP-HPLC with spectrophotometric detection was used. For calculating log P, the fragmental methods ACD/log P, CLOGP, and KOWWIN, the atom-based approach XLOGP, and the whole-molecule approach QLOGP were applied.

Comparison of ligand-based and structure-based 3D-QSAR approaches: a case study on (aryl-)bridged 2-aminobenzonitriles inhibiting HIV-1 reverse transcriptase.

Ligand- (GRIND) and structure-based (GLUE/GRIND) 3D-QSAR approaches were compared for 55 (aryl-)bridged 2-aminobenzonitriles inhibiting HIV-1 reverse transcriptase (HIV-1 RT). The ligand-based model was built from conformers selected by in vacuo minimization. The available X-ray structure of 3v in complex with HIV-1 RT allowed comparative structure-based calculations using the new docking software GLUE for conformer selection.

The impact of lipophilicity in drug research: a case report on beta-blockers.

The key importance of lipophilicity in bio-studies is discussed for beta-blockers. Examples of their lipophilicity-dependent pharmacological properties including pharmacokinetic, pharmacodynamic and clinical aspects are reviewed. Comprehensive lipophilicity compilations of beta-blockers are lacking so far.

GRIND/ALMOND investigations on CysLT1 receptor antagonists of the quinolinyl(bridged)aryl type.

One of the current routes in developing antiasthmatics is CysLT(1) receptor antagonism. For a training set of 54 CysLT(1) receptor antagonists of the quinolinyl(bridged)aryl type we developed chemometric QSAR models applying GRID independent descriptors (=GRIND). PLS analysis resulted in a two-component model explaining 67% of the variance for CysLT(1) receptor binding (r2=0.

Chemometric studies on the bactericidal activity of quinolones via an extended VolSurf approach.

An extended VolSurf approach, that additionally includes SHAPE descriptors, was applied to a dataset of 55 quinolones. Bactericidal activity was measured at Bayer AG, Germany, for Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis). Chemometric analysis was first approached via a classical VolSurf approach.

KATP channel openers: structure-activity relationships and therapeutic potential.

ATP-sensitive potassium channels (K(ATP) channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K(ATP) channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening.

Molecular modeling and QSAR studies on K(ATP) channel openers of the benzopyran type.

The present paper describes our molecular modeling and quantitative structure-activity relationships (QSARs) studies on K(ATP) channel openers (KCOs) of the benzopyran type. In the first part we performed molecular modeling investigations with seven benzopyrans, varied at the C3- and C4-positions, in order to understand which molecular features at these positions are essentially effecting the biological activity. The impact of C6-substitution on biological activity was studied in the second part via HANSCH analysis.

Suitability of molecular descriptors for database mining. A comparative analysis.

Database mining methods rely on the molecular descriptors used to characterize a structural database. In the present investigation, five different types of descriptors (log P, UNITY fingerprints, ISIS keys, VolSurf, and GRIND) are applied to characterize various databases (n = 1007, 100, and 229) comprising drugs almost exclusively. The validity of the descriptors is comparatively analyzed via principal component analysis and its hierarchical variant, consensus principal component analysis.

GBR compounds and mepyramines as cocaine abuse therapeutics: chemometric studies on selectivity using grid independent descriptors (GRIND).

Cocaine is one of the most widely abused drugs in the industrial world. Substantial evidence has accumulated that the dopamine transporter (DAT) is a key target for cocaine regarding its reinforcing effects. This work describes the application of chemometric methods to a data set of 54 N(1)-benzhydryl-oxy-alkyl-N(4)-phenyl-alk(en)yl-piperazines (GBR compounds) and chemically related mepyramines as putative candidates in cocaine abuse therapy.

6-Sulfonylchromenes as highly potent K(ATP)-channel openers.

We synthesized K(ATP)-channel openers (KCOs) composed of the 4-pyridonechromene moiety of bimakalim (1) and a variety of sulfonyl-containing 6-substituents 4-29. Dilator potencies were measured in rat aorta and trachea. In both test systems the KCOs exhibit potency ranges of roughly 3 log units.