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

• Published in: Chemical physics letters Vol. 777; no. C; p. 138727
• Main Authors: Mamontov, Eugene, Cheng, Yongqiang, Daemen, Luke L., Kolesnikov, Alexander I., Ramirez-Cuesta, Anibal J., Ryder, Matthew R., Stone, Matthew B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 16.08.2021; Elsevier
• Subjects: DFT calculations; Inelastic neutron scattering; Microscopic dynamics; Molecular drugs; Quasielastic neutron scattering; Research Paper; Microscopic dynamics; Molecular drugs; Quasielastic neutron scattering; DFT calculations; Inelastic neutron scattering; microscopic dynamics; quasielastic neutron scattering; inelastic neutron scattering
• ISSN: 0009-2614; 1873-4448; 0009-2614
• DOI: 10.1016/j.cplett.2021.138727

[Display omitted] •Apilimod and tetrandrine reportedly work better than remdesivir against SARS-CoV-2.•We find that apilimod and tetrandrine show much reduced methyl rotational barriers.•Low potential barriers lead to pronounced quantum effects at low temperatures.•Low potential barriers lead to fast methyl rotation at physiological temperatures.•Screening studies of the energy landscape can help identify promising drug candidates. 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.