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Automated design of ligands to polypharmacological profiles


The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand–target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.

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Figure 1: Adaptive drug design.
Figure 2: Polypharmacology profiles of designed ligands.
Figure 3: Reducing α 1 anti-target activity by evolutionary design.
Figure 4: Evolution of D4 dopamine ligands from donepezil.


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This work is supported by SULSA (HR07019), the BBSRC Doctoral Training Programme, the BBSRC Pathfinder (BB/FOF/PF/15/09) and the BBSRC Follow On Fund schemes (BB/J010510/1) (A.L.H.), the University of Dundee’s Pump Priming Fund for Translational Medical Research (I.H.G. and A.L.H.) and by grants from the National Institutes of Health (NIH) supporting drug discovery receptor pharmacology (B.L.R.) and the NIH grant MH082441 (W.C.W.). The chemical synthesis and informatics benefits from the infrastructure investments from the Wellcome Trust Strategic Award (WT 083481). We thank J. Overington for StARlite and ChEMBL. We wish to thank D. Murugesan for compound purification and C. Means and T. Rhodes for helping with the open field, hole-board and zero-maze tests. We also wish to thank C. Elms and J. Zhou for their support in the husbandry and generation of the mice used for behavioural testing. We also wish to thank F. Y. Li for customizing the software configuration for the hole-board tests. Some of the equipment used in the behavioural testing was purchased with a grant from the North Carolina Biotechnology Center. B.L.R. also received support from the Michael Hooker Chair of Pharmacology.

Author information




A.L.H. devised the method, developed the algorithm and designed the study. J.B. coded the algorithm and undertook the calculations. G.R.B. developed the databases. A.L.H. and J.B. with I.H.G., G.F.R. and K.A. selected the compounds for synthesis. I.H.G., G.F.R. and K.A. designed the synthetic routes and G.F.R. and K.A. undertook the chemical synthesis. L.A.W. purified and analysed several of the compounds. B.L.R. and V.S. designed the empirical tests for the synthesized compound predictions, analysed and interpreted the results and performed the experiments. X.-P.H. performed the 5-HT2B functional assays and the hERG assays. M.F.S. conducted the dopamine D2 and D4 functional assays. K.D.R. designed the drug metabolism and pharmacokinetics studies and analysed the results. S.N., L.S. and F.R.C.S. carried out the DMPK experiments. For the behavioural experiments, D.B.C. created the mice in which the Pcsk7 gene was disrupted. A.P. and N.G.S. verified the Pcsk7 deletion in many tissues including brain, and then backcrossed the mice onto a C57BL/6 background. W.C.W. designed the studies; R.M.R. and A.I.S. conducted the experiments and analysed the results; W.C.W., R.M.R., A.I.S., D.B.C., A.P. and N.G.S. interpreted the findings; A.L.H. and B.L.R. wrote the manuscript; I.H.G. wrote the synthetic methods with help from G.F.R., K.A. and L.A.W.; W.C.W. and R.M.R. wrote the behavioural section of the manuscript and J.B., V.S., W.C.W. and R.M.R. prepared the figures. All the authors discussed the results and commented on the manuscript.

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Correspondence to Bryan L. Roth or Andrew L. Hopkins.

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Competing interests

A.L.H., J.B. and G.R.B. are shareholders in Ex Scientia Ltd, a University of Dundee spin-off company that has licensed the technology.

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This file contains Supplementary Figures 1-13, Supplementary Methods, Supplementary Tables 1-12 and Supplementary References – see contents for further details. (PDF 12182 kb)

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Besnard, J., Ruda, G., Setola, V. et al. Automated design of ligands to polypharmacological profiles. Nature 492, 215–220 (2012).

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