From Protein Structure to Function with Bioinformatics.pdf

178 N.J. Burgoyne and R.M. Jacksonof support vector machines to improve the sensitivity of predictions (Tong et al.2008). Most recently, the performance of the method was shown to be littleaffected if apo structures rather than holo structures (the two having substantialconformational differences) were analysed (Murga et al. 2008). While the methodis powerful in its independence of availability or not of homologous sequences,it should be emphasised that it is only suitable for predictions of catalytic sites,not binding sites in general.7.4.3 Predictions of DruggabilityThe current range of proteins that are both relevant to disease and can be successfullytargeted by small molecule drugs is restricted to only a small number of proteinfamilies, and these can be extended by sequence similarity to only 5% of theproteins in the human proteome (Hopkins and Groom 2002). Finding other potentialdrug targets by experimental means such as high-throughput ligand screeningis a time-consuming process, and one of the main expenses in the drug discoveryprocess with 60% of drug discovery projects failing because the target is deemednot to be druggable (Brown and Superti-Furga 2003). Predicting whether a bindingsite can bind a typical drug-like molecule is one of the newest challenges in proteinstructural biology (Cheng et al. 2007).One recent approach has extended the geometry-based pocket detection algorithmsdescribed earlier with estimates of protein surface desolvation and valuesdescribing the curvature of the protein surface (Cheng et al. 2007). These are combinedwith estimates of typical protein-ligand interaction properties (such as thecorrelation between ligand molecular weight and buried protein surface) to createa single empirical-based parameter for drug binding ability. A similar potential hasbeen generated from the analysis of drug binding pockets by nuclear magneticresonance (Hajduk et al. 2005). Both these potentials agree that large, easily desolvated,pockets which include other sub-pockets are favoured for the binding ofdrug-like molecules.7.4.4 Annotation of Ligand Binding SitesPredicting protein binding sites and their small molecule druggability is an importantfirst step in the drug development process. Predicting which of the few ligandsin libraries approaching tens of thousands of compounds are likely to be selective,potent, and make effective drugs is the next important step. This is another problemwhere understanding the properties of protein surfaces can also help. Typicallythese problems are addressed initially by virtual ligand screening involving dockingor pharmacophore matching methods to a ligand library (Oledzki et al. 2006).However, energetic-based annotations of ligand binding sites can help visualise and