Molecular dynamics simulations in drug discovery and pharmaceutical development
Salo-Ahen, Outi M.H.; Alanko, Ida; Bhadane, Rajendra; Alexandre, Alexandre M.; Honorato, Rodrigo Vargas; Hossain, Shakhawath; Juffer, André H.; Kabedev, Aleksei; Lahtela-Kakkonen, Maija; Larsen, Anders Støttrup; Lescrinier, Eveline; Marimuthu, Parthiban; Mirza, Muhammad Usman; Mustafa, Ghulam; Nunes-Alves, Ariane; Pantsar, Tatu; Saadabadi, Atefeh; Singaravelu, Kalaimathy; Vanmeert, Michiel
(2021) Processes, volume 9, issue 1, pp. 1 - 60
(Article)
Abstract
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 pos-sibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples
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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 substan-tially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.
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Keywords: Binding free energy, Computational pharmaceutics, Computer-aided drug design, Con-formational ensemble, Drug formulations, Drug targets, Enhanced sampling methods, Ligand binding kinetics, Membrane interactions, Protein flexibility, Bioengineering, Chemical Engineering (miscellaneous), Process Chemistry and Technology
ISSN: 2227-9717
Publisher: MDPI AG
Note: Funding Information: This work was supported by the BioExcel CoE (www.bioexcel.eu), a project funded by the European Horizon 2020 program under grant agreements 675728 and 823830 (R.V.H.); the ?bo Akademi University research mobility program in the research profiling area of Drug Development and Diagnostics (R.B.); ?bo Akademi University research grant (A.S.); Tor, Joe and Pentti Borg?s Foundation in 2020 (P.M.); the Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (Capes, process number 88881.162167/2017-01), the Alexander von Humboldt Foundation, and the Klaus Tschira Foundation (A.N.A.); the European Union?s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 839230 and Orion Research Foundation sr. (T.P.); Vinnova (Dnr 2017-02690), the European Research Council Grant 638965 (A.K. and S.H.) and the Academy of Finland grant number 315824 (M.L.-K.). Funding Information: Funding: This work was supported by the BioExcel CoE (www.bioexcel.eu), a project funded by the European Horizon 2020 program under grant agreements 675728 and 823830 (R.V.H.); the Åbo Akademi University research mobility program in the research profiling area of Drug Development and Diagnostics (R.B.); Åbo Akademi University research grant (A.S.); Tor, Joe and Pentti Borg’s Foundation in 2020 (P.M.); the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes, process number 88881.162167/2017-01), the Alexander von Humboldt Foundation, and the Klaus Tschira Foundation (A.N.A.); the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 839230 and Orion Research Foundation sr. (T.P.); Vinnova (Dnr 2017-02690), the European Research Council Grant 638965 (A.K. and S.H.) and the Academy of Finland grant number 315824 (M.L.-K.). Funding Information: Acknowledgments: We acknowledge the NordForsk Nordic POP (Patient Oriented Products) university consortium, the joint Drug Development and Diagnostics research profiling area of the University of Turku and Åbo Akademi University, and the science program of the Swedish Drug Delivery Forum (SDDF). A.N.A. thanks Rebecca Wade for suggestions on the manuscript (drug binding kinetics section). M.L.-K. acknowledges CSC—IT Center for Science, Finland, for computational resources. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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