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EFMC-ISMC 2012 XXIInd Medicinal Chemistry Symposium

Workshop Abstract

Monday September 3rd, 12.15

Presenter: Dr Tien Luu, Advisory Scientist

New Computational Methods for Fragment Based Lead Discovery

Fragment Based Drug Design (FBDD) has developed significantly over the past decade and is now widely accepted as a viable method of hit identification and lead optimisation. The smaller size of fragments (molecular weight < 250 Da) allows a smaller sample of library compounds to sample a large chemical space and provide higher hit rates than screening of larger compound libraries.  Ideally, each lead generated from FBDD should fit into the binding site, be chemically tractable, and have good binding affinity/specificity to the protein. In this talk, we present some new, easy to use computational methods for fragment based lead discovery supporting the typical workflow:

1. PLACE – place an initial fragment in the correct binding position and orientation to the protein binding
2. GROW – grow the fragment by chemical functionalization with in situ reactions, taking into account the protein environment
3. REPLACE – replace portions of the lead molecules to generate more ideas

A number of examples will be presented to demonstrate these methods, illustrating the use of common chemical reactions to ensure that the generated leads are chemically tractable, the ability to allow specific interactions with protein side-chains, inclusion of full implicit-solvent-based energy simulations and even selective flexibility of protein residue side-chains.


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