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Review

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

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Pharmaceutical Sciences Laboratory (Pharmacy), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland
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Structural Bioinformatics Laboratory (Biochemistry), Åbo Akademi University, Tykistökatu 6 A, Biocity, FI-20520 Turku, Finland
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Faculty of Science-Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands
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Swedish Drug Delivery Forum (SDDF), Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
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Biocenter Oulu & Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7 A, FI-90014 Oulu, Finland
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School of Pharmacy, University of Eastern Finland, FI-70210 Kuopio, Finland
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Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark
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Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, B-3000 Leuven, Belgium
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Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Heidelberg Institute for Theoretical Studies (HITS), Schloß-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
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Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
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Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
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Turku Computer Science and Informatics, Department of Future Technologies, University of Turku, FI-20520 Turku, Finland
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Authors to whom correspondence should be addressed.
Processes 2021, 9(1), 71; https://doi.org/10.3390/pr9010071
Received: 21 November 2020 / Revised: 23 December 2020 / Accepted: 26 December 2020 / Published: 30 December 2020
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies. View Full-Text
Keywords: binding free energy; computational pharmaceutics; computer-aided drug design; conformational ensemble; drug formulations; drug targets; enhanced sampling methods; ligand binding kinetics; protein flexibility; membrane interactions binding free energy; computational pharmaceutics; computer-aided drug design; conformational ensemble; drug formulations; drug targets; enhanced sampling methods; ligand binding kinetics; protein flexibility; membrane interactions
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MDPI and ACS Style

Salo-Ahen, O.M.H.; Alanko, I.; Bhadane, R.; Bonvin, A.M.J.J.; Honorato, R.V.; Hossain, S.; Juffer, A.H.; Kabedev, A.; Lahtela-Kakkonen, M.; Larsen, A.S.; Lescrinier, E.; Marimuthu, P.; Mirza, M.U.; Mustafa, G.; Nunes-Alves, A.; Pantsar, T.; Saadabadi, A.; Singaravelu, K.; Vanmeert, M. Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development. Processes 2021, 9, 71. https://doi.org/10.3390/pr9010071

AMA Style

Salo-Ahen OMH, Alanko I, Bhadane R, Bonvin AMJJ, Honorato RV, Hossain S, Juffer AH, Kabedev A, Lahtela-Kakkonen M, Larsen AS, Lescrinier E, Marimuthu P, Mirza MU, Mustafa G, Nunes-Alves A, Pantsar T, Saadabadi A, Singaravelu K, Vanmeert M. Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development. Processes. 2021; 9(1):71. https://doi.org/10.3390/pr9010071

Chicago/Turabian Style

Salo-Ahen, Outi M.H., Ida Alanko, Rajendra Bhadane, Alexandre M.J.J. Bonvin, Rodrigo V. Honorato, Shakhawath Hossain, André H. Juffer, Aleksei Kabedev, Maija Lahtela-Kakkonen, Anders S. Larsen, Eveline Lescrinier, Parthiban Marimuthu, Muhammad U. Mirza, Ghulam Mustafa, Ariane Nunes-Alves, Tatu Pantsar, Atefeh Saadabadi, Kalaimathy Singaravelu, and Michiel Vanmeert. 2021. "Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development" Processes 9, no. 1: 71. https://doi.org/10.3390/pr9010071

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