Biomedical subjects

Wijnand T M Mooij

Publications and source records attributed to Wijnand T M Mooij.

4 recordsLinked to original sources

PubMed2006

Automated protein-ligand crystallography for structure-based drug design.

An approach to automate protein-ligand crystallography is presented, with the aim of increasing the number of structures available to structure-based drug design. The methods we propose deal with the automatic interpretation of diffraction data for targets with known protein structures, and provide easy access to the results. Central to the system is a novel procedure that fully automates the placement of ligands into electron density maps. Automation provides an objective way to structure solution, whereas manual placement can be rather subjective, especially for data of low to medium resolution. Ligands are placed by docking into electron density, whilst taking care of protein-ligand interactions. The ligand fitting procedure has been validated on both public domain and in-house examples. Some of the latter deal with cocktails of low-molecular weight compounds, as used in fragment-based drug discovery by crystallography. For such library-screening experiments we show that the method can automatically identify which of the compounds from a cocktail is bound.

Crystallography, X-Ray↗

PubMed2005

General and targeted statistical potentials for protein-ligand interactions.

We present a novel atom-atom potential derived from a database of protein-ligand complexes. First, we clarify the similarities and differences between two statistical potentials described in the literature, PMF and Drugscore. We highlight shortcomings caused by an important factor unaccounted for in their reference states, and describe a new potential, which we name the Astex Statistical Potential (ASP). ASP's reference state considers the difference in exposure of protein atom types towards ligand binding sites. We show that this new potential predicts binding affinities with an accuracy similar to that of Goldscore and Chemscore. We investigate the influence of the choice of reference state by constructing two additional statistical potentials that differ from ASP only in this respect. The reference states in these two potentials are defined along the lines of Drugscore and PMF. In docking experiments, the potential using the new reference state proposed for ASP gives better success rates than when these literature reference states were used; a success rate similar to the established scoring functions Goldscore and Chemscore is achieved with ASP. This is the case both for a large, general validation set of protein-ligand structures and for small test sets of actives against four pharmaceutically relevant targets. Virtual screening experiments for these targets show less discrimination between the different reference states in terms of enrichment. In addition, we describe how statistical potentials can be used in the construction of targeted scoring functions. Examples are given for cdk2, using four different targeted scoring functions, biased towards increasingly large target-specific databases. Using these targeted scoring functions, docking success rates as well as enrichments are significantly better than for the general ASP scoring function. Results improve with the number of structures used in the construction of the target scoring functions, thus illustrating that these targeted ASP potentials can be continuously improved as new structural data become available.

Binding Sites↗

PubMed2002

Crystal structure prediction of small organic molecules: a second blind test.

The first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy. A maximum of three predictions were allowed per molecule. The results showed two correct predictions for the first molecule, four for the second molecule and none for the third molecule (which had torsional flexibility). The correct structure was often present in the sorted low-energy lists from the participants but at a ranking position greater than three. The use of non-indexed powder diffraction data was investigated in a secondary test, after completion of the ab initio submissions. Although no one method can be said to be completely reliable, this workshop gives an objective measure of the success and failure of current methodologies.

Journal Article↗

PubMedDate not supplied

Virtual screening using protein-ligand docking: avoiding artificial enrichment.

This study addresses a number of topical issues around the use of protein-ligand docking in virtual screening. We show that, for the validation of such methods, it is key to use focused libraries (containing compounds with one-dimensional properties, similar to the actives), rather than "random" or "drug-like" libraries to test the actives against. We also show that, to obtain good enrichments, the docking program needs to produce reliable binding modes. We demonstrate how pharmacophores can be used to guide the dockings and improve enrichments, and we compare the performance of three consensus-ranking protocols against ranking based on individual scoring functions. Finally, we show that protein-ligand docking can be an effective aid in the screening for weak, fragment-like binders, which has rapidly become a popular strategy for hit identification. All results presented are based on carefully constructed virtual screening experiments against four targets, using the protein-ligand docking program GOLD.

Ligands↗