Abstract Details

Poster 20: Scaffold Hopping for Aromatic Rings. Can MM Compete with QM?

Sree Vadlamudi1, Tim Cheeseright1, Martin Slater1, Mark Mackey1
1Cresset BioMolecular Discovery Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AX, UK
Bioisostere transformations are an important part of the medicinal chemist’s toolkit. Bioisosteres of side chains can be used to provide guidance on lead optimisation, suggesting ways to improve the ADMET and physicochemical properties of a molecule whilst maintaining its activity. Conversely, bioisosteric transformation of molecular cores is an often-used technique to find new routes through often congested patent spaces. Increasing attention is being paid to computational techniques for suggesting bioisosteres. However, to be useful, it is imperative that the ranking method suggests isosteric replacements that work in a biological system.

Our technique uses the molecular interaction fields (1) of the parent molecule and assesses replacements in the context in which they will be synthesized. This enables the differing steric and electronic effects of potential new scaffolds to be used. An added bonus of our method is that replacements for terminal substituents can be considered alongside more central moieties enabling its use in growing fragments and lead optimization as well as lead generation. The method is embodied in the software product “sparkV10” and will be presented together with a number of case studies.

Direct comparison with a recently published method (2) utilizing quantum mechanical calculations (NEAT) shows that sparkV10 produces similar results in an equivalent experiment. This demonstrates that QM methods are not required to perform scaffold hopping in heteroaromatic systems. We discuss how results can be improved using features in sparkV10 that are not possible with the QM method, and advantages and disadvantages of the NEAT database versus the previously published VEHICLe database.

(1) Cheeseright T, Mackey M, Rose S, Vinter A. “Molecular field extrema as descriptors of biological activity: definition and validation.”, J. Chem Inf. Mod., 2006, 665. Cheeseright TJ, Mackey MD, Scoffin RA. “High content pharmacophores from molecular fields: a biologically relevant method for comparing and understanding ligands.”, Curr. Comput. Aided Drug Des. 2011 7(3), 190-205.
(2) Tu M, Rai BK, Mathiowetz AM, Didiuk M, Pfefferkorn JA, Guzman-Perez A, Benbow J, Guimarães CR, Mente S, Hayward MM, Liras S. “Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template.” , J. Chem Inf. Mod., 2012 May 25; 52(5) 1114-23.

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