Hydration-Induced Disorder Lowers the Energy Barriers for Methyl Rotation in Drug Molecules

Eugene Mamontov; Yongqiang Cheng; Luke L. Daemen; Alexander I. Kolesnikov; Anibal J. Ramirez-Cuesta; Matthew R. Ryder; Matthew B. Stone

doi:10.1021/acs.jpclett.0c02642

Hydration-Induced Disorder Lowers the Energy Barriers for Methyl Rotation in Drug Molecules

Eugene Mamontov, Yongqiang Cheng, Luke L. Daemen, Alexander I. Kolesnikov, Anibal J. Ramirez-Cuesta, Matthew R. Ryder, Matthew B. Stone

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

The thermally activated dynamics of methyl groups are important for biochemical activity as they allow for a more efficient sampling of the energy landscape. Here, we compare methyl rotations in the dry and variously hydrated states of three primary drugs under consideration to treat the recent coronavirus disease (COVID-19), namely, hydroxychloroquine and its sulfate, dexamethasone and its sodium diphosphate, and remdesivir. We find that the main driving force behind the considerable reduction in the activation energy for methyl rotations in the hydrated state is the hydration-induced disorder in the methyl group local environments. Furthermore, the activation energy for methyl rotations in the hydration-induced disordered state is much lower than that in an isolated drug molecule, indicating that neither isolated molecules nor periodic crystalline structures can be used to analyze the potential landscape governing the side group dynamics in drug molecules. Instead, only the explicitly considered disordered structures can provide insight.

Original language	English
Pages (from-to)	10256-10261
Number of pages	6
Journal	Journal of Physical Chemistry Letters
Volume	11
Issue number	23
DOIs	https://doi.org/10.1021/acs.jpclett.0c02642
State	Published - Dec 3 2020

Funding

The neutron scattering experiments at Oak Ridge National Laboratory’s (ORNL’s) Spallation Neutron Source (SNS) were supported by the Scientific User Facilities Division, Office of Science (Basic Energy Sciences), U.S. Department of Energy (DOE). The authors acknowledge the U.S. Department of Energy (DOE) Office of Science (Basic Energy Sciences) for research funding. M.R.R. acknowledges the National Energy Research Scientific Computing Center (NERSC), a U.S. Department of Energy (DOE) Office of Science User Facility, operated under contract no. DE-AC02-05CH11231, for access to supercomputing resources. Computing resources were also made available through the VirtuES and the ICEMAN projects, funded by the Laboratory Directed Research and Development program at ORNL. The authors thank Dr. Mark D. Lumsden for valuable discussion and Rhonda Moody for the dedication to obtaining sample materials.

Funders	Funder number
Scientific User Facilities Division
U.S. Department of Energy
Office of Science
Basic Energy Sciences
Oak Ridge National Laboratory
Laboratory Directed Research and Development
National Energy Research Scientific Computing Center	DE-AC02-05CH11231

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10.1021/acs.jpclett.0c02642

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abstract = "The thermally activated dynamics of methyl groups are important for biochemical activity as they allow for a more efficient sampling of the energy landscape. Here, we compare methyl rotations in the dry and variously hydrated states of three primary drugs under consideration to treat the recent coronavirus disease (COVID-19), namely, hydroxychloroquine and its sulfate, dexamethasone and its sodium diphosphate, and remdesivir. We find that the main driving force behind the considerable reduction in the activation energy for methyl rotations in the hydrated state is the hydration-induced disorder in the methyl group local environments. Furthermore, the activation energy for methyl rotations in the hydration-induced disordered state is much lower than that in an isolated drug molecule, indicating that neither isolated molecules nor periodic crystalline structures can be used to analyze the potential landscape governing the side group dynamics in drug molecules. Instead, only the explicitly considered disordered structures can provide insight.",

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AU - Ramirez-Cuesta, Anibal J.

AU - Ryder, Matthew R.

AU - Stone, Matthew B.

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AB - The thermally activated dynamics of methyl groups are important for biochemical activity as they allow for a more efficient sampling of the energy landscape. Here, we compare methyl rotations in the dry and variously hydrated states of three primary drugs under consideration to treat the recent coronavirus disease (COVID-19), namely, hydroxychloroquine and its sulfate, dexamethasone and its sodium diphosphate, and remdesivir. We find that the main driving force behind the considerable reduction in the activation energy for methyl rotations in the hydrated state is the hydration-induced disorder in the methyl group local environments. Furthermore, the activation energy for methyl rotations in the hydration-induced disordered state is much lower than that in an isolated drug molecule, indicating that neither isolated molecules nor periodic crystalline structures can be used to analyze the potential landscape governing the side group dynamics in drug molecules. Instead, only the explicitly considered disordered structures can provide insight.

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Hydration-Induced Disorder Lowers the Energy Barriers for Methyl Rotation in Drug Molecules

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