Automated design of ligands to polypharmacological profiles

Jérémy Besnard, Gian Filippo Ruda, Vincent Setola, Keren Abecassis, Ramona M. Rodriguiz, Xi-Ping Huang, Suzanne Norval, Maria F. Sassano, Antony I. Shin, Lauren A. Webster, Frederick R. C. Simeons, Laste Stojanovski, Annik Prat, Nabil G. Seidah, Daniel B. Constam, G. Richard Bickerton, Kevin D. Read, William C. Wetsel, Ian H. Gilbert, Bryan L. Roth () and Andrew L. Hopkins ()
Additional contact information
Jérémy Besnard: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Gian Filippo Ruda: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Vincent Setola: NIMH Psychoactive Drug Screening Program, The University of North Carolina Chapel Hill School of Medicine
Keren Abecassis: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Ramona M. Rodriguiz: Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical School
Xi-Ping Huang: NIMH Psychoactive Drug Screening Program, The University of North Carolina Chapel Hill School of Medicine
Suzanne Norval: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Maria F. Sassano: The University of North Carolina Chapel Hill School of Medicine
Antony I. Shin: Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical School
Lauren A. Webster: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Frederick R. C. Simeons: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Laste Stojanovski: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Annik Prat: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), affiliated with the University of Montreal, Montreal, Quebec, H2W 1R7, Canada
Nabil G. Seidah: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), affiliated with the University of Montreal, Montreal, Quebec, H2W 1R7, Canada
Daniel B. Constam: Ecole Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19, CH-1015 Lausanne, Switzerland
G. Richard Bickerton: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Kevin D. Read: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
William C. Wetsel: Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical School
Ian H. Gilbert: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Bryan L. Roth: NIMH Psychoactive Drug Screening Program, The University of North Carolina Chapel Hill School of Medicine
Andrew L. Hopkins: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK

Nature, 2012, vol. 492, issue 7428, 215-220

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/nature11691

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