Molecular visualization in the rational drug design process

Keil, Matthias; Marhöfer, Richard J.; Rohwer, Andreas; Selzer, Paul M.; Brickmann, Jürgen; Korb, Oliver; Exner, Thomas E.

doi:10.2741/3398

Cited by 9 publications

(4 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, 18 of these belong to protein families for which 3D structural information including ligands or even drugs is available (e.g., N-(4-Methoxybenzyl)-N′-(5-Nitro-1,3-Thiazol-2-YI)Urea and Carbidopa). This opens the route not only for classical biochemical studies but also for structure-based drug discovery approaches [29] , [46] , [47] . For instance, among the 18 candidate proteins, small molecule scaffolds exist for methionine aminopeptidase targeting cancer [48] and malaria [49] , N-myristoyl transferase against fungal infections [50] and Rac-GTPase against cancer [51] .…”

Section: Discussionmentioning

confidence: 99%

A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni

Caffrey

Rohwer²,

Oellien³

et al. 2009

PLoS ONE

View full text Add to dashboard Cite

Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for ‘druggable’ protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen.

show abstract

Section: Discussionmentioning

confidence: 99%

A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni

Caffrey

Rohwer²,

Oellien³

et al. 2009

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…[38] Very large compound data sets can be tested without purchasing or synthesis, enabling a fast way to explore unknown parts of the chemical space. [39]…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds

Engels

Beyer

Fernández³

et al. 2010

ChemMedChem

View full text Add to dashboard Cite

Apicomplexan parasites encompass several human-pathogenic as well as animal-pathogenic protozoans like Plasmodium falciparum, Toxoplasma gondii, and Eimeria tenella. E. tenella is the causative agent of coccidiosis a disease of chickens, which causes tremendous economic losses to the world poultry industry. Considerable increase of drug resistance makes it necessary to develop and pursue new therapeutic strategies. Cyclin-dependent kinases (CDKs) are key molecules in the regulation of the cell cycle and are therefore prominent target proteins in parasitic diseases. Bioinformatic analysis revealed four potential CDK-like proteins of which one -E. tenella CDKrelated kinase 2 (EtCRK2) -is already cloned, expressed and characterized. [1] Using the CDK specific inhibitor Flavopiridol in EtCRK2 enzyme assays and schizont maturation assays we could chemically validate CDK-like proteins as potential drug targets. An X-ray crystal structure of human CDK2 (HsCDK2) served as template to built protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP-binding site between EtCRK2 and HsCDK2 as well as chicken CDK3 have been addressed for the optimization of selective ATPcompetitive inhibitors. Virtual screening and "wet-bench" high throughput screening campaigns on large compound libraries resulted in an initial set of hit compounds. These compounds were further analyzed and characterized leading to a set of four promising lead compounds inhibiting EtCRK2.

show abstract

“…For this purpose, the solvent accessible surface may be approximated by mimicking all atoms as hard spheres. Moreover, local patches of the solute surface can be used for highlighting the properties of the atoms below (31,32). An example for the construction of such three-dimensional shapes which coloring accounts for local binding capabilities is illustrated in figure 4.…”

Section: Hydrophilic and Hydrophobic Solvationmentioning

confidence: 99%

“…While the shape of the molecular surface accounts for sterical fitting, proper matching of the local atomic properties may be illustrated by the surface coloring. The latter issue involves complementary partial charges, the matching of hydrogen bond donors to acceptors and the assembly of hydrophobic domains (32). During the last two decades, this approach to the modeling of protein-ligand complexes became a standard tool which is accessible to common PCs and interactive computation.…”

Section: Hydrophilic and Hydrophobic Solvationmentioning

confidence: 99%

On the role of the solvent in biosystems: atomistic insights from computer simulations

Zahn

2009

Front Biosci

View full text Add to dashboard Cite

This review describes recent progress of atomistic simulations to promote the understanding of the role of the solvent in biophysics and biochemistry. Fundamental aspects of aqueous solutions and their importance for the rationalization of biomolecular arrangements and metabolic transport are discussed. Many of these insights were obtained from molecular dynamics simulations performed during the last three decades. In combination with quantum mechanical descriptions this approach nowadays advanced to a reliable tool for the investigation of biochemical reactions. Apart from passive coordination of the reactants, the solvent studies may also address proton transfer over chains of hydrogen bonded molecules.

show abstract

Molecular visualization in the rational drug design process

Cited by 9 publications

References 59 publications

A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni

A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni

Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds

On the role of the solvent in biosystems: atomistic insights from computer simulations

Contact Info

Product

Resources

About