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IADE: a system for intelligent automatic design of bioisosteric analogs

Abstract

IADE, a software system supporting molecular modellers through the automatic design of non-classical bioisosteric analogs, scaffold hopping and fragment growing, is presented. The program combines sophisticated cheminformatics functionalities for constructing novel analogs and filtering them based on their drug-likeness and synthetic accessibility using automatic structure-based design capabilities: the best candidates are selected according to their similarity to the template ligand and to their interactions with the protein binding site. IADE works in an iterative manner, improving the fitness of designed molecules in every generation until structures with optimal properties are identified. The program frees molecular modellers from routine, repetitive tasks, allowing them to focus on analysis and evaluation of the automatically designed analogs, considerably enhancing their work efficiency as well as the area of chemical space that can be covered. The performance of IADE is illustrated through a case study of the design of a nonclassical bioisosteric analog of a farnesyltransferase inhibitor—an analog that has won a recent “Design a Molecule” competition.

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Notes

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    The authors recognize that there may be certain implementation details that were obvious to us but may be unclear from our description. We are willing to work with scientists trying to re-implement the code if there are sins of omission concerning the methodology.

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Acknowledgments

The authors would like to acknowledge help of colleagues Peter Gedeck, Nikolaus Stiefl and Marc Litherland who helped with the implementation of IADE. Several colleagues at Novartis acted as test users and early adopters, particularly Simona Cotesta, Paulette Greenidge, Hanneke Jansen, Anna Vulpetti, Bernard Pirard and Finton Sirockin. We would like to thank also Cresset Group for help with the use of command line FieldAlign and for organizing the “Design a Molecule” competition.

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Correspondence to Peter Ertl.

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Ertl, P., Lewis, R. IADE: a system for intelligent automatic design of bioisosteric analogs. J Comput Aided Mol Des 26, 1207–1215 (2012). https://doi.org/10.1007/s10822-012-9609-3

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Keywords

  • IADE
  • Bioisosteric design
  • Scaffold hopping
  • Chemical space
  • Automated iterative drug design