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Modeling chemical reactions for drug design

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Abstract

Chemical reactions are involved at many stages of the drug design process. This starts with the analysis of biochemical pathways that are controlled by enzymes that might be downregulated in certain diseases. In the lead discovery and lead optimization process compounds have to be synthesized in order to test them for their biological activity. And finally, the metabolism of a drug has to be established. A better understanding of chemical reactions could strongly help in making the drug design process more efficient. We have developed methods for quantifying the concepts an organic chemist is using in rationalizing reaction mechanisms. These methods allow a comprehensive modeling of chemical reactivity and thus are applicable to a wide variety of chemical reactions, from gas phase reactions to biochemical pathways. They are empirical in nature and therefore allow the rapid processing of large sets of structures and reactions. We will show here how methods have been developed for the prediction of acidity values and of the regioselectivity in organic reactions, for designing the synthesis of organic molecules and of combinatorial libraries, and for furthering our understanding of enzyme-catalyzed reactions and of the metabolism of drugs.

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Acknowledgements

Able coworkers, mentioned in the references, have embarked into the unknown domain of modeling chemical reactivity and chemical reactions. I owe much gratitude to their dedication. Our work has been funded by the Bundesministerium für Forschung und Technologie (BMFT), the Bundesministerium für Bildung und Forschung (BMBF), the Deutsche Forschungsgemeinschaft (DFG), ICI plc, UK, Pfizer, Groton, CT, USA, and Pfizer, Sandwich, UK. To all these institutions I am deeply indebted. I also thank Elsevier MDL, San Ramon, CA, USA for making their databases available to us.

Over many years I have been inspired by Yvonne Martin’s great scientific interest and her exploring questions. As a case in point: More than 15 years ago she asked me to come up with some methods for estimating synthetic accessibility. Unfortunately, it took us quite some time to find the time and the right people to achieve this goal.

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  1. Computer-Chemie-Centrum, Universität Erlangen-Nürnberg, 91052, Erlangen, Germany

    Johann Gasteiger

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  1. Johann Gasteiger
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Correspondence to Johann Gasteiger.

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Gasteiger, J. Modeling chemical reactions for drug design. J Comput Aided Mol Des 21, 33–52 (2007). https://doi.org/10.1007/s10822-006-9097-4

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