Design of a virtual fragment library for docking studies

• Grant number: 09/05893-8
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: August 03, 2009
• End date: September 09, 2009
• Field of knowledge: Interdisciplinary Subjects
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Carlos Alberto Montanari
• Visiting researcher: Peter W. Kenny
• Visiting researcher institution: AstraZeneca, United Kingdom, England
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Solvent mapping of proteins was described in 1996 as an approach to locate binding sites on protein surfaces. The computational analog involves calculating interaction energies for a library of small molecular probes at various locations on the protein surface. Computational solvent mapping can be used both to guide molecular design and to assess 'druggability' of target proteins. The probes used in computational solvent mapping tend to be very simple molecules, capable of presenting only a limited range of molecular recognition features to target proteins. The proposal is to design a library of small, prototypical molecular probes for mapping protein surfaces using existing docking tools. Probes will be selected to present diverse molecular recognition features (e.g. heterocycles; acylsulfonamide anions) to target proteins. The library will be organized using structural relationships between probes such as shape similarity, charge type and shared framework with different number of hydrogen bonding groups (e.g. pyrrole and pyrazole). Unsymmetrical relationships can also be defined such as the extent that one probe is contained in another (e.g. acetic acid; benzoic acid). Relationships between probe molecules can also be used to organize docking output. The library will be evaluated by its ability to mimic individual binding interactions in a range of protein-ligand complexes. Inability to mimic particular binding interactions will be used to refine the library. (AU)