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Binding Free Energy Calculation Using Quantum Mechanics Aimed for Drug Lead Optimization

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Quantum Mechanics in Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2114))

Abstract

The routine use of in silico tools is already established in drug lead design. Besides the use of molecular docking methods to screen large chemical libraries and thus prioritize compounds for purchase or synthesis, more accurate calculations of protein–ligand binding free energy has shown the potential to guide lead optimization, thus saving time and resources. Theoretical developments and advances in computing power have allowed quantum mechanical-based methods applied to calculations on biomacromolecules to be increasingly explored and used, with the purpose of providing a more accurate description of protein–ligand interactions and an enhanced level of accuracy in the calculation of binding affinities. It should be noted that the quantum mechanical formulation includes, in principle, all contributions to the energy, considering terms usually neglected in molecular mechanics force fields, such as electronic polarization, metal coordination, and covalent binding; moreover, quantum mechanical approaches are systematically improvable. By treating all elements and interactions on equal footing, and avoiding the need of system-dependent parameterizations, they provide a greater degree of transferability. In this review, we illustrate the increasing relevance of quantum mechanical methods for binding free energy calculation in the context of structure-based drug lead optimization, showing representative applications of the different approaches available.

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Acknowledgments

This work was supported by the National Agency for the Promotion of Science and Technology (ANPCyT) (PICT-2014-3599 and PICT-2017-3767). CNC thanks Molsoft LLC (San Diego, CA) for providing an academic license for the ICM program. The author thanks the National System of High Performance Computing (Sistemas Nacionales de Computación de Alto Rendimiento, SNCAD), the Centro de Computación de Alto Rendimiento (Computational Centre of High Performance Computing, CeCAR), and the Centro de Cálculo de Alto Desempeño (Universidad Nacional de Córdoba) for granting use of their computational resources.

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Authors and Affiliations

  1. Computational Drug Design and Biomedical Informatics Laboratory, Translational Medicine Research Institute (IIMT), CONICET-Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina

    Claudio N. Cavasotto

  2. Austral Institute for Applied Artificial Intelligence, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina

    Claudio N. Cavasotto

  3. Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina

    Claudio N. Cavasotto

  4. Facultad de Ingeniería, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina

    Claudio N. Cavasotto

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  1. Claudio N. Cavasotto
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Correspondence to Claudio N. Cavasotto .

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  1. Evotec (UK) Ltd., Abingdon, Oxfordshire, UK

    Alexander Heifetz

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Cavasotto, C.N. (2020). Binding Free Energy Calculation Using Quantum Mechanics Aimed for Drug Lead Optimization. In: Heifetz, A. (eds) Quantum Mechanics in Drug Discovery. Methods in Molecular Biology, vol 2114. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0282-9_16

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  • DOI: https://doi.org/10.1007/978-1-0716-0282-9_16

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0281-2

  • Online ISBN: 978-1-0716-0282-9

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