Drug research is often termed as searching for a needle in a haystack. Virtual screening is widely recognised as a valuable tool to effectively reduce the size of the 'haystack' by about one order of magnitude. In the presentation of Miklos Vargyas, Chemaxon on the Cheminformatics & Modelling Hub, he discusses in detail techniques that can further improve the efficiency of the virtual screening procedure.
Dr. Vargyas’s recent work has focused on topological pharmacophore similarity based search where only a set of known active 2D structures is known. The pharmacophores of these structures are analysed by perceiving the pharmacophoric characteristic of each individual atom. Pharmacophore patterns are transformed into a topological cross-correlation histogram. These correlation histograms are molecular descriptors that represent the pharmacophoric character of structures in a mathematically tractable form. Proximities (metrics) like the Euclidean distance and the Tanimoto coefficient are applied to estimate the dissimilarity between two such descriptors.
The canonic formulae of the proximities are extended with weights and other parameters to help bias the metrics behaviour when comparing two compounds. Parameters are optimized in an automated training process that uses a subset of the target library and a subset of the known active structures. The optimized proximities are then passed on to an independent validation stage, which evaluates by calculating the enrichment ratio achieved within the virtual screening process.
Generating the structural fingerprint is much faster than creating the pharmacophore fingerprint (in which pharmacophore perception takes longer time), and the storage requirement of the structural fingerprint is also significantly smaller. Dr. Vargas shows for a number of preliminary tested cases that the use of the more costly pharmacophore fingerprint is beneficial when the diversity of the library is over 0.45.
Dr. Vargas shows that optimized virtual screening is capable of reducing the size of the 'haystack' by another order of magnitude (in some cases an even higher reduction is achieved) and that it can also lead to scaffold hopping when a pharmacophore fingerprint is used. The method is generic enough to adapt to other molecular descriptors and metrics.
You can listen to the full talk of Miklos Vargyas with audio on the Cheminformatics Hub at eCheminfo.com
Barry Hardy
www.douglasconnect.com
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