Biomedical subjects

Raimund Mannhold

Publications and source records attributed to Raimund Mannhold.

14 recordsLinked to original sources

PubMed2006

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.g. relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. Structure-activity relationships of the main chemical classes of KCOs are discussed.

Animals↗

PubMed2005

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 9.10 for compound 4c. Comparison of data for smooth muscle relaxation and binding shows preferentially higher pEC(50)s for the former. In cardiomyocytes, pK(D) values range from 4.21 for 3e to 8.16 for 4c. 3D-QSAR analysis resulted in PLS models of two latent variables for all three activities with determination coefficients of 0.97 (smooth muscle relaxation) and 0.94 (smooth muscle cells- and cardiomyocytes-binding). Internal validation yielded q(2) values of 0.69, 0.66, and 0.64. The carbonyl on the N-4 substituent, the hydrogen bond acceptor at C-6, the five-membered ring at N-4, and the gem-dimethyls mainly guide strong binding and strong smooth muscle relaxation.

Adenosine Triphosphate↗

PubMed2005

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. In this paper, partial least squares discriminant analysis is applied to derive the chemical features guiding AT(1) and AT(2) selectivity or mixed AT(1)/AT(2) receptor binding. The method can be used to modulate AT(1) versus AT(2) selectivity. Concerns that unopposed stimulation of the AT(2) receptor might produce adverse effects initiated a search for new balanced antagonists. Moreover, it can serve as a fast filtering procedure in database searches. Finally, some relevant pharmacokinetics and metabolic properties of the database of 53 compounds are calculated using the VolSurf and MetaSite software to allow the simultaneous characterization of pharmacodynamic and pharmacokinetics properties of the chemical space of angiotensin II receptor antagonists.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

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. RESULTS: Quality of calculations significantly differs depending on the subset under consideration. For database compounds 01-48, comprising alkyl and aryl substitution in 4- and 5-position, the fragmental methods ACD/log P, CLOGP, and KOWWIN perform significantly better than the atom-based approach XLOGP and the whole-molecule method QLOGP. For database compounds 49-68, comprising formyl and acyl substitution in 4- and 5-position, superiority of the whole-molecule method QLOGP over the substructure-based approaches is observed. The strong underestimation of log P for compounds 49-68 probably indicates hidden physicochemical phenomena resulting from the juxtaposition of the acyl and dithiole moieties. CONCLUSIONS: All calculation methods included in this study need a thorough refinement to adequately cope with particular solvation behavior suspected to prevail in formyl- or acyl-DTT and DTO, which represent a chemical class of high pharmacological interest.

Calorimetry↗

PubMed2005

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. Both models were validated via statistics and via virtual receptor sites (VRS) considering pharmacophoric regions and mutual distances, which were also compared with experimental evidence. The statistics show slight superiority of the structure-based approach in terms of fitting and prediction. By encoding relevant molecular interaction fields (MIF) into pharmacophoric regions, 10 such regions were derived from both models; they all fit the real receptor except HBD2. Also mutual distances highly agree between the real site and both VRS. Although distances from the structure-based approach are closer to the real receptor, present data prove the validity of the ligand-based GRIND approach.

Binding Sites↗

PubMed2005

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. LogP calculations with 10 programs for 30 clinically relevant beta-blockers are presented for the first time in this review.

Adrenergic beta-Antagonists↗

PubMed2005

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.

ATP-Binding Cassette Transporters↗

PubMed2004

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=0.67, SDEC = 0.47, q2=0.54). GRIND variables 11-50 and 22-55 are responsible for high-affinity binding; variable 11-62 is detrimental. The predictivity of the above chemometric model is tested with a set of 69 CysLT(1) receptor antagonists, exhibiting varying chemical similarity to the training set. Nearly 50% of the test set are quite well predicted. The quality of prediction coincides in part with chemical subclassification: phenylene bridged compounds are quite well predicted; for structures with bridging heterocycles predictions are rather poor. For explaining the outlier behavior, a PLS discriminant analysis including the training set and the strongest outliers of the test set was performed. The scores plot of discriminant PLS shows an almost complete separation between the two subsets. A PLS coefficients plot explains which GRIND variables are important for the discrimination between the training set and the outliers of the test set.

Asthma↗

PubMed2004

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. The following descriptors were found most important: bactericidal activity particularly increases with high values of the best volume (BV11(OH2)) and the minimum energy (Emin1(OH2)) of the water probe, high values of the integy moment (ID(DRY)) of the lipophilic probe, and high values of the hydrophilic region (W(O)) of the hydrogen bond acceptor probe. Best volume (BV31(OH2)) of the water probe and best volume (BV12(DRY)) and lipophilic regions (D(DRY)) of the lipophilic probe as well as H-bonding capacity derived with the CO probe (HB(O)) are inversely related to activity. PLS analysis yields a five-component model with an r(2) of 0.83 and a q(2) of 0.43 after variable selection via fractional factorial design (FFD). Chemometric modeling could be improved by including newly derived SHAPE descriptors, which were merged with the VolSurf descriptors and subjected to PLS analysis. The global model of this extended VolSurf approach is optimal with two components and exhibits a significantly improved statistical quality; a marginally reduced r(2) (0.75 versus 0.83) is more than compensated by a highly improved predictivity with a q(2) of 0.63 versus 0.43. To prove model quality, external prediction of seven test set quinolones was performed. The precise prediction of all test set molecules nicely demonstrates the robustness and statistical significance of the obtained chemometric model using the extended VolSurf approach.

Anti-Bacterial Agents↗

PubMed2004

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. Functionally, K(ATP) channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K(ATP) channels. 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), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols.

ATP-Binding Cassette Transporters↗

PubMed2002

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. Both pharmacodynamic and pharmacokinetic aspects of database mining are treated. For pharmacodynamic aspects, clustering behavior achieved with the different descriptors is tested on the chemically homogeneous beta-blockers, benzodiazepines, and penicillins and on the chemically more diverse class I antiarrhythmics. The following ranking is observed: UNITY fingerprints > ISIS keys and GRIND > VolSurf > log P. Regarding information content, the CPCA superweight plot indicates similarity between fingerprints and ISIS keys as well as between VolSurf and log P, while GRIND differs from all the remaining descriptors. Solubility data and blood/brain barrier penetrating behavior serve as test cases for pharmacokinetic aspects. Comparison of the descriptors applied to these data reveals that VolSurf has the most realistic and consistent behavior, GRIND shows intermediate behavior, while UNITY fingerprints and ISIS keys are not well suited for pharmacokinetic profiling. From this comparative analysis, we conclude that VolSurf descriptors exhibit particular advantages in treating pharmacokinetic aspects; UNITY fingerprints, ISIS keys, and GRIND descriptors are of special value for tackling pharmacodynamic aspects of database mining. The parameter log P is of limited applicability in database mining because of rather poor reliability and lack of completeness of data.

Computing Methodologies↗

PubMed2002

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. The aim of the study is to gain insight into the structural requirements that determine the affinity of the data set molecules to the DAT and the serotonin transporter (SERT) as well as their inhibitory potency on dopamine uptake. The compounds in the dataset are described using the recently developed GRID independent descriptors (GRIND), which allow one to obtain fast three-dimensional quantitative structure-activity relationship models without the need of aligning and superimposing the structures; the results are interpreted in a convenient pharmacophoric-like fashion. In the first part of the work, the selectivity of the database molecules for DAT binding vs dopamine reuptake inhibition is investigated. In the second part, the selectivity of the compounds for DAT binding vs SERT binding is studied. In both cases, significant models are obtained, which define the structural features responsible for the respective selectivity profiles. Moreover, the information has potential interest for the design of new derivatives with improved selectivity.

Carrier Proteins↗

PubMed2002

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. The 6-N-phenyl-N-methylsulfonamido derivative 24 shows the highest potency. In rat aorta the potency spectrum ranges from a pEC(50) value of 8.76 to 5.68; in rat trachea it ranges from 8.01 to 4.99. On average, the dilator activity is about 0.8 log units stronger in the aorta. Aortic relaxation by chromene 13 is markedly retarded, the clinical relevance of which (e.g., preventing tachycardia) remains to be clarified. Binding affinities were determined in myocardial membranes and aortic smooth muscle cells of the rat. The affinity spectrum in myocardial membranes ranges from a pK(D) of 7.83 to 5.18; the highest affinity in aortic smooth muscle cells is measured for compound 28 (pK(D) = 8.55), whereas the lowest affinity is measured for 4 (pK(D) = 4.51). Significant selectivities discriminating between K(ATP)-channels of different organs could not be detected. PLS analysis yielded no significant correlation between vasodilator activity in aorta and chemical descriptors (GRIND). Compounds 13, 24, and 28 represent the most potent KCOs of the 4-pyridonechromene type published so far. Their 6-substituents exhibit a phenyl ring with a congruent conformational orientation in relation to the sulfonylchromene. From SAR data and conformational analysis we postulate that these new 6-substituents extend the binding site for chromene KCOs. Correspondingly, we assume that the receptor area exhibits two separate interaction sites with the capacity to bind 6-substituents: (a) one site interacting with negatively polarized partial structures (e.g., CN, NO(2), SO(2)) and (b) one spatially restricted site enabling favorable pi-interactions.

Adenosine Triphosphate↗

PubMed2002

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. For this purpose physicochemical properties (charge distributions, lowest unoccupied molecular orbital (LUMO) energies, desolvation energies, volumes and dipole moments) were calculated for a set of 50 C6-varied benzopyrans. A QSAR equation was developed showing a relationship between the vasodilator activity and the direction of the dipole vector of the ligands. The conclusion can be drawn that a direct interaction between the C6-substituents and the receptor structure is not of primary importance. However, the substitutents influence the orientation of the whole ligand approaching the binding site. An unfavorably oriented ligand cannot bind to the binding site, thus exhibiting weak activity.

Benzopyrans↗