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Multiscale methods in drug design bridge chemical and biological complexity in the search for cures

Nature Reviews Chemistry volume 2, Article number: 0148 (2018) Cite this article

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Abstract

Drug action is inherently multiscale: it connects molecular interactions to emergent properties at cellular and larger scales. Simulation techniques at each of these different scales are already central to drug design and development, but methods capable of connecting across these scales will extend our understanding of complex mechanisms and our ability to predict biological effects. Improved algorithms, ever-more-powerful computing architectures and the accelerating growth of rich data sets are driving advances in multiscale modelling methods capable of bridging chemical and biological complexity from the atom to the cell. Particularly exciting is the development of highly detailed, structure-based physical simulations of biochemical systems, which can now reach experimentally relevant timescales for large systems and, at the same time, achieve unprecedented accuracy. In this Perspective, we discuss how emerging data-rich, physics-based multiscale approaches are on the cusp of realizing their long-promised impact on the discovery, design and development of novel therapeutics. We highlight emerging methods and applications in this growing field and outline how different scales can be combined in practical modelling and simulation strategies.

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Figure 1: Multiscale structure-based and physics-based methods bridging from atoms to cells.
Figure 2: Multiscale simulation methods to predict drug metabolism by cytochrome P450 enzymes.

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Acknowledgements

Support from NIH DP2 OD007237 and NIH P41 GM103426 to R.E.A. is gratefully acknowledged. R.E.A. thanks Pek Ieong, Ludovic Autin and Benjamin Jagger for assistance in figure preparation. A.J.M. thanks EPSRC for support (EP/M022609/1 (for CCP-BioSim see www.ccpbiosim.ac.uk) and EP/M015378/1) and BBSRC (BB/M000354/1). A.J.M. thanks co-workers, including Christopher Woods, Christine Bathelt, Sarah Rouse, Richard Lonsdale and Mark Sansom, for help in the preparation of the figures.

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  1. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, US

    Rommie E. Amaro

  2. Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, UK

    Adrian J. Mulholland

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  1. Rommie E. Amaro
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  2. Adrian J. Mulholland
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All authors contributed equally to the preparation of this manuscript.

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Correspondence to Rommie E. Amaro or Adrian J. Mulholland.

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Competing interests

R.E.A. is a co-founder, a Scientific Advisory Board member and has equity interest in Actavalon, Inc. A.J.M has no competing interests.

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Amaro, R., Mulholland, A. Multiscale methods in drug design bridge chemical and biological complexity in the search for cures. Nat Rev Chem 2, 0148 (2018). https://doi.org/10.1038/s41570-018-0148

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