Issue 43, 2021

Deep generative design with 3D pharmacophoric constraints

Abstract

Generative models have increasingly been proposed as a solution to the molecular design problem. However, it has proved challenging to control the design process or incorporate prior knowledge, limiting their practical use in drug discovery. In particular, generative methods have made limited use of three-dimensional (3D) structural information even though this is critical to binding. This work describes a method to incorporate such information and demonstrates the benefit of doing so. We combine an existing graph-based deep generative model, DeLinker, with a convolutional neural network to utilise physically-meaningful 3D representations of molecules and target pharmacophores. We apply our model, DEVELOP, to both linker and R-group design, demonstrating its suitability for both hit-to-lead and lead optimisation. The 3D pharmacophoric information results in improved generation and allows greater control of the design process. In multiple large-scale evaluations, we show that including 3D pharmacophoric constraints results in substantial improvements in the quality of generated molecules. On a challenging test set derived from PDBbind, our model improves the proportion of generated molecules with high 3D similarity to the original molecule by over 300%. In addition, DEVELOP recovers 10× more of the original molecules compared to the baseline DeLinker method. Our approach is general-purpose, readily modifiable to alternate 3D representations, and can be incorporated into other generative frameworks. Code is available at https://github.com/oxpig/DEVELOP.

Graphical abstract: Deep generative design with 3D pharmacophoric constraints

Supplementary files

Article information

Article type
Edge Article
Submitted
03 May 2021
Accepted
18 Oct 2021
First published
25 Oct 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 14577-14589

Deep generative design with 3D pharmacophoric constraints

F. Imrie, T. E. Hadfield, A. R. Bradley and C. M. Deane, Chem. Sci., 2021, 12, 14577 DOI: 10.1039/D1SC02436A

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