The COVID-19 pandemic has accelerated the study of drugs, most notably ivermectin and more recently Paxlovid (PF-07321332) which is in phase III clinical trials with experimental data showing covalent binding to the viral protease Mpro. Theoretical developments of catalytic site-directed docking support thermodynamically feasible non-covalent binding to Mpro. Here we show that Paxlovid binds non-covalently at regions other than the catalytic sites with energies stronger than reported and at the same binding site as the ivermectin B1a homologue, all through theoretical methodologies, including blind docking. We volumetrically characterize the non-covalent interaction of the ivermectin homologues (avermectins B1a and B1b) and Paxlovid with the mMpro monomer, through molecular dynamics and scaled particle theory (SPT). Using the fluctuation-dissipation theorem (FDT), we estimated the electric dipole moment fluctuations at the surface of each of complex involved in this study, with similar trends to that observed in the interaction volume. Using fluctuations of the intrinsic volume and the number of flexible fragments of proteins using anisotropic and Gaussian elastic networks (ANM+GNM) suggests the complexes with ivermectin are more dynamic and flexible than the unbound monomer. In contrast, the binding of Paxlovid to mMpro shows that the mMpro-PF complex is the least structurally dynamic of all the species measured in this investigation. The results support a differential molecular mechanism of the ivermectin and PF homologues in the mMpro monomer. Finally, the results showed that Paxlovid despite beingbound in different sites through covalent or non-covalent forms behaves similarly in terms of its structural flexibility and volumetric behaviour.
|Journal||Computational Biology and Chemistry|
|State||Published - Aug 2022|
Bibliographical noteFunding Information:
In this sense, multiple authors have suggested continuing studies of ivermectin and its interactions with the various targets of SARS-CoV-2 in order to use it as a model to guide efforts towards the development of new compounds and treatment strategies ( Patil et al., 2022; Jeffreys et al., 2022; Delandre et al., 2022 ) as has already been done ( Rabie, 2021 ). In fact, ivermectin is currently being investigated in the UK as part of the Platform Randomized Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE), the world's largest clinical trial of possible COVID-19 treatments for recovery at home and in other non-hospital settings. This trial is supported by UKRI/DHSC (UK Research and Innovation (UKRI)- Department of Health and Social Care (DHSC)) ( https://www.principletrial.org/ ).
© 2022 Elsevier Ltd
- Volume Molar
- Volume fluctuation