SCOL : The Structural Classification of Ligands

"Students look at the support, honours, prizes, and rewards lavished on X-ray crystallographers and molecular geneticists and they want to be there. By working within these fashionable fields, scientific creativity, adapted to a flourishing technology, can still exist and be recognised. Outside of these fashionable directions, however, although survival is possible, recognition is extremely difficult." Robert G. Shulman

Project Overview

Objectives

The objective of the SCOL project is to produce a global hierarchical clustering of all the available small molecules and protein ligands using measures of structural, chemical and biological 'similarity' between molecules. At a broad level, this hierarchical classification should reflect biological and chemical intuitions about the major classes of molecule and their broad physical and chemical characteristics. At a more detailed level of classification, structurally and chemically similar molecules should be grouped together. This classification system should prove useful for diverse studies, from the gross assessment of metabolic evolution to ligand binding studies. The ultimate aim is to assist in the process of drug discovery and lead compound identification. A distinct sub project of SCOL is the derivation of a set of 'representative' or 'non-redundant' compounds for input into more detailed structural and functional studies.

Goals / Independent Sub-Tasks

The overall objectives of SCOL can be broken down into several different but overlapping activities. Some tasks are purely technical, while others require substantial background research. Other tasks will require the investigation and development of novel areas of research. Many of the preliminary subtasks have already been completed by various different groups, and may or may not be directly applicable to the development of SCOL. Some or all of these tasks may reflect my ignorance and you are invited to fix this with out delay! No doubt you can think of many other interesting and/or practical sub tasks, which you can add by joining the project!

Task List:
• Obtain a comprehensive database of small molecule structures.
• Implement libraries of chemical / physiochemical properties of small molecules and atoms.
• Assess the state of predictive software for the automatic analysis of small molecules. e.g. predicting hydrophobicity, pK, etc.
• Implement visualisation interface to various chemical structures and physical properties.
• Implement similarity measures between small molecules based on combinations of structural, physical and chemical properties.
• Develop clustering strategies over the similarly measures (similarity matrices) in order to assess the most useful notions of 'similarity' between small molecules and at what level of detail these measures are most appropriate.
• Assess the best 'ontology' for the classification. e.g. is a DAG more appropriate than a strict hierarchy?
• Develop visualisation interface to hierarchical clusterings.
• Assess the overlap between biological notions of 'good clusters' versus the purely algorithmic 'goodness of clusters' given the different similarity measures and clustering algorithms used.
• Investigate issues of modularity in small molecule structure, using both information from the perspective of cluster splitting and detailed knowledge of modular assembly derived from metabolic pathways.
• Investigate potential 'homologous' relationships between structurally similar ligands with biological analysis of the ligand.
• Investigate 'biological' measures of similarity derived from the evolution of ligand binding proteins, and assess the overlap with SCOL.
• Investigate the potential predictive power of SCOL.
• Develop new potential drugs using SCOL.

Related Projects / Resources

This list is by no means exhaustive (although I see no reason why it shouldn't be). If you would like to be included (or removed) or if you have a link you recommend, please contact me.

Links Page

Literature

A collection of more or less relevant literature. This is not supposed to be a static collection, but should grow as understanding, scope, knowledge and research does. If you have suggested literature, please contact me. Please note that this section is in it't infancy (please don't be upset if I miss you out!)

Reading

Project License

This project is not 'open' in the strict sense. To work on SCOL you must first agree to the BiO License, a summary of which is given hear.

Hosting This project is hosted at Bioinformatics.Org and it is thanks to the open policy of BiO that projects like this can exist. Go to the project page

"However, individuals choosing such an unfashionable direction must have the passionate vision enabling them to bear considerable neglect and be able to settle for less recognition. Young biochemists have low morale not because their chances to flourish are not described clearly and honestly by caring elders, but because the opportunities available require that their passions be subordinated to fashionable directions that emphasize technical activities at the expense of biological goals." Hard Days in the Trenches, Robert G. Shulman