Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
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Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development. / Salo-Ahen, Outi M. H.; Alanko, Ida; Bhadane, Rajendra; Bonvin, Alexandre M. J. J.; Honorato, Rodrigo Vargas; Hossain, Shakhawath; Juffer, Andre H.; Kabedev, Aleksei; Lahtela-Kakkonen, Maija; Larsen, Anders Stottrup; Lescrinier, Eveline; Marimuthu, Parthiban; Mirza, Muhammad Usman; Mustafa, Ghulam; Nunes-Alves, Ariane; Pantsar, Tatu; Saadabadi, Atefeh; Singaravelu, Kalaimathy; Vanmeert, Michiel.
In: Processes, Vol. 9, No. 1, 71, 2021.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
AU - Salo-Ahen, Outi M. H.
AU - Alanko, Ida
AU - Bhadane, Rajendra
AU - Bonvin, Alexandre M. J. J.
AU - Honorato, Rodrigo Vargas
AU - Hossain, Shakhawath
AU - Juffer, Andre H.
AU - Kabedev, Aleksei
AU - Lahtela-Kakkonen, Maija
AU - Larsen, Anders Stottrup
AU - Lescrinier, Eveline
AU - Marimuthu, Parthiban
AU - Mirza, Muhammad Usman
AU - Mustafa, Ghulam
AU - Nunes-Alves, Ariane
AU - Pantsar, Tatu
AU - Saadabadi, Atefeh
AU - Singaravelu, Kalaimathy
AU - Vanmeert, Michiel
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - binding free energy
KW - computational pharmaceutics
KW - computer-aided drug design
KW - conformational ensemble
KW - drug formulations
KW - drug targets
KW - enhanced sampling methods
KW - ligand binding kinetics
KW - protein flexibility
KW - membrane interactions
KW - COMPUTER-SIMULATIONS
KW - INFORMATION-DRIVEN
KW - MEMBRANE
KW - PROTEINS
KW - INSIGHTS
U2 - 10.3390/pr9010071
DO - 10.3390/pr9010071
M3 - Review
VL - 9
JO - Processes
JF - Processes
SN - 2227-9717
IS - 1
M1 - 71
ER -
ID: 257745272