Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine

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

doi:10.1016/j.cplett.2021.138727

Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine

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

9 Scopus citations

Abstract

A recent screening study highlighted a molecular compound, apilimod, for its efficacy against the SARS-CoV-2 virus, while another compound, tetrandrine, demonstrated a remarkable synergy with the benchmark antiviral drug, remdesivir. Here, we find that because of significantly reduced potential energy barriers, which also give rise to pronounced quantum effects, the rotational dynamics of the most dynamically active methyl groups in apilimod and tetrandrine are much faster than those in remdesivir. Because dynamics of methyl groups are essential for biochemical activity, screening studies based on the computed potential energy profiles may help identify promising candidates within a given class of drugs.

Original language	English
Article number	138727
Journal	Chemical Physics Letters
Volume	777
DOIs	https://doi.org/10.1016/j.cplett.2021.138727
State	Published - Aug 16 2021

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 of ORNL, managed by UT-Battelle, LLC for the U.S. Department of Energy under contract DE-AC05-00OR22725. The authors thank Dr. Mark D. Lumsden for valuable discussions. The authors are grateful to Rhonda Moody for dedication to obtaining sample materials.

Funders	Funder number
ORNL Laboratory Research and Development Program	DE-AC05-00OR22725
Scientific User Facilities Division
U.S. Department of Energy
Office of Science
Basic Energy Sciences
Oak Ridge National Laboratory
National Energy Research Scientific Computing Center	DE-AC02- 05CH11231

Keywords

DFT calculations
Inelastic neutron scattering
Microscopic dynamics
Molecular drugs
Quasielastic neutron scattering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cplett.2021.138727

Cite this

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title = "Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine",

abstract = "A recent screening study highlighted a molecular compound, apilimod, for its efficacy against the SARS-CoV-2 virus, while another compound, tetrandrine, demonstrated a remarkable synergy with the benchmark antiviral drug, remdesivir. Here, we find that because of significantly reduced potential energy barriers, which also give rise to pronounced quantum effects, the rotational dynamics of the most dynamically active methyl groups in apilimod and tetrandrine are much faster than those in remdesivir. Because dynamics of methyl groups are essential for biochemical activity, screening studies based on the computed potential energy profiles may help identify promising candidates within a given class of drugs.",

keywords = "DFT calculations, Inelastic neutron scattering, Microscopic dynamics, Molecular drugs, Quasielastic neutron scattering",

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T1 - Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine

AU - Mamontov, Eugene

AU - Cheng, Yongqiang

AU - Daemen, Luke L.

AU - Kolesnikov, Alexander I.

AU - Ramirez-Cuesta, Anibal J.

AU - Ryder, Matthew R.

AU - Stone, Matthew B.

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AB - A recent screening study highlighted a molecular compound, apilimod, for its efficacy against the SARS-CoV-2 virus, while another compound, tetrandrine, demonstrated a remarkable synergy with the benchmark antiviral drug, remdesivir. Here, we find that because of significantly reduced potential energy barriers, which also give rise to pronounced quantum effects, the rotational dynamics of the most dynamically active methyl groups in apilimod and tetrandrine are much faster than those in remdesivir. Because dynamics of methyl groups are essential for biochemical activity, screening studies based on the computed potential energy profiles may help identify promising candidates within a given class of drugs.

KW - DFT calculations

KW - Inelastic neutron scattering

KW - Microscopic dynamics

KW - Molecular drugs

KW - Quasielastic neutron scattering

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Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine

Abstract

Funding

Keywords

UN SDGs

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