Ivermectin and Doxycycline combination as a promising anti-viral drug candidate: an in-silico and DFT study
et al., In Silico Pharmacology, doi:10.1007/s40203-026-00576-w, Aug 2021 (preprint)
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
|
In silico study showing strong binding affinity of ivermectin and doxycycline for SARS-CoV-2 main protease 3CLpro, and increased binding affinity for the combination of both.
76 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N773, Dengue38,74,75 , HIV-175, Simian virus 4076, Zika38,77,78 , West Nile78, Yellow Fever79,80, Japanese encephalitis79, Chikungunya80, Semliki Forest virus80, Human papillomavirus58, Epstein-Barr58, BK Polyomavirus81, and Sindbis virus80.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins73,75,76,82 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing39, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination42,83, shows dose-dependent inhibition of wildtype and omicron variants37, exhibits dose-dependent inhibition of lung injury63,68, may inhibit SARS-CoV-2 via IMPase inhibition38, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation10, inhibits SARS-CoV-2 3CLpro55, may inhibit SARS-CoV-2 RdRp activity1,29, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages62, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation84, may interfere with SARS-CoV-2's immune evasion via ORF8 binding5, may inhibit SARS-CoV-2 by disrupting CD147 interaction85-88, may inhibit SARS-CoV-2 attachment to lipid rafts via spike NTD binding3, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1960,89, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage9, significantly mitigates bleomycin-induced pulmonary fibrosis by reducing collagen accumulation and inflammatory cell infiltration61, improves oxidative stress markers while suppressing myofibroblast proliferation61, may minimize SARS-CoV-2 induced cardiac damage41,49, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation90, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses2, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways36, increases Bifidobacteria which play a key role in the immune system91, has immunomodulatory52 and anti-inflammatory72,92 properties, and has an extensive and very positive safety profile93.
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Rana et al., 5 Aug 2021, peer-reviewed, 5 authors.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection
doi:10.21203/rs.3.rs-755838/v1
In the present study, we have described how by using molecular docking and molecular dynamics (MD) simulation studies the combination drug of ivermectin and doxycycline can be used as a potential inhibitor for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) virus. In lieu of unavailability of specific cure of coronavirus disease of 2019 (COVID-19) till now various possibilities for individual and combination drugs have been explored by the medical practitioners/scientists for the remedial purpose of CoV-2 infections. 3C-like protease (3CL pro ) is the main protease of SARS-CoV-2 virus which plays an essential role in mediating viral replication in the human body. 3CL pro protein can serve as an attractive drug target. In this work, we have studied drug: 3CL pro interactions by in-silico molecular docking and MD simulation approaches. Common and easily available antiviral drugs ivermectin, doxycycline and their combination can regulate 3CL pro protein's function due to its easy inhibition.
docked pose position (Table 2 ). For doxycycline: protein complex, pose 7 is the better interacted position with the binding affinity of -6.4 kcal/mol, dreiding energy; 6,063.5, dipole moment; 6.104 Debye, inhibition constant; 2.0 X 10 -5 M and 7 number of hydrogen bonds (Table 2 ). Best pose of the donor-acceptor surface with their possible hydrogen bonding and hydrophobic interactions 3D and 2D view are shown in Figure 3b . Our result shows that out of two possible ligand drug structures, ivermectin represents the best potentiality to inhibit with the SARS 3CL pro (6LU7) by its best docking affinity compared to the doxycycline. Good binding mode of interactions of ivermectin: protein complex also verified by its less binding energy, minimum inhibition constant value as compared to doxycycline. Both the drug molecules showed good stability as a complex with the targeted protein. These drug molecules also satisfy the required drug likeness properties according to Ro5, Veber etc. rules, polar surface areas and logP values. RMSD corresponds to any change in the conformational stability of the protein: drug complex and in the protein dynamics. RMSD of the free protein and protein: ligand complex have been simulated to 100000 psby using MD simulations. RMSD and RMSF have been measured by using the GROMACS module at an interval of 1000 ps. RMSD variation of apo 3CL pro lies in the range from 0.08 to 0.16Å. Ivermectin: 3CL pro , doxycycline: 3CL pro , ivermectin+doxycycline: 3CL..
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