Abstract Details

Poster 52: The Origins of 3D Shape in Drug-Like Molecules

Nicholas C. Firth1, Nathan Brown1, Julian Blagg1
1The Institute of Cancer Research
Recently there has been a trend in drug design to tackle molecular targets classed on the edge of druggable space [1], for example protein-protein interactions. This trend is driven by the increasing numbers of molecular targets on the edge of druggable space for which the evidence supporting disease-linkage, both genetic and pharmacological is strong. The move towards these challenging molecular targets has also been associated with the desire for compounds with significant three-dimensional (3D) character [2]. Molecules with 3D character also increase the chance of higher solubility due to the nature of their solid-state crystal packing. We have shown that current libraries are poorly populated with molecules having significant 3D character [3], especially those libraries used for fragment based drug discovery [4] and the enrichment of fragment libraries with molecules having 3D character is a current effort in the medicinal chemistry community [5]. The hypothesis behind this enrichment effort is that 3D fragments can be used to build 3D molecules [5].
In this work we will present our recently developed computational method: Plane of Best Fit (PBF) to analyse the three-dimensional (3D) character of molecular conformations [3]. This method generates a plane of best fit for a conformation of a given molecule and calculates the distance of each heavy atom from the plane in ångströms and outputs the average of these distances.

The PBF method will be used to analyse fragment contributions to the overall 3D character of a molecule in order to study the molecular origins of 3D shape in drug-like compounds. For example, molecules from the ChEMBL database will be fragmented into rings and linkers, and 3D coordinates will be generated [CORINA]. The corresponding PBF score and frequency of occurrence for each ring and linker will be generated and used, in comparison with the corresponding whole molecule PBF scores, to understand which molecular components have inherent 3D character and the extent to which 3D character arises from the combination of 2D components.

Molecular scaffolds will also be generated for each molecule using an objective and invariant method [6] and a set of replacement scaffolds selected using multi-criteria decision analysis, focusing on the PBF score to analyse the applicability of the PBF score to scaffold hopping methodologies. Scaffolds of varying 3D character will be used to investigate the extent to which a 3D scaffold increases the likelihood of a 3D molecule.


[1] J.P.Overington, B. Al-Lazikani, A.L. Hopkins, How many drug targets are there?, Nature Rev. Drug Disc., 2006 5(12), 993-996.
[2] D.C. Fry. Drug-Like Inhibitors of Protein-Protein Interactions: A Structural Examination of Effective Protein Mimicry, Curr. Protein Pept. Sci., 2008, 9(3):240-247.
[3] N.C. Firth, N. Brown, J. Blagg, Plane of Best Fit: A Novel Method to Characterize the Three-Dimensionality of Molecules. J. Chem. Inf. Model, 2012, 52(10), 2516-2525.
[4] A.W. Hung, A. Ramek, Y. Wang, T. Kaya, J.A. Wilson, P.A. Clemons, D.W. Young, Route to three-dimensional fragments using diversity-oriented synthesis. Proc. Nat. Acad. Sci., 2011, 108(17) 6799-6804.
[5] http://www.3dfrag.org/
[6] S.R. Langdon, N. Brown, J. Blagg, Identifying Medicinal Chemistry Relevant Scaffolds for Scaffold Hopping, UK-QSAR Autumn Meeting 2012, Cambridge.

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