Tinocordiside from Tinospora cordifolia (Giloy) May Curb SARS-CoV-2 Contagion by Disrupting the Electrostatic Interactions between Host ACE2 and Viral S-Protein Receptor Binding Domain

Abstract

Background: SARS-CoV-2 has been shown to bind the host cell ACE2 receptor through its spike protein receptor binding domain (RBD), required for its entry into the host cells. Objective: We have screened phytocompounds from a medicinal herb, Tinospora cordifolia, for their capacities to interrupt the viral RBD and host ACE2 interactions. Method: We employed molecular docking to screen phytocompounds in T. cordifolia against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy. Results: ‘Tinocordiside’ docked very well at the center of the interface of ACE2-RBD complex, and was found to be well stabilized during MD simulation. Tinocordiside incorporation significantly decreased electrostatic component of binding free energies of ACE2-RBD complex (23.5 and 17.10 kcal/mol in the trajectories without or with the ligand, respectively). As the basal rate constant of protein association is in the order of 5, (105 to 106 M-1 S-1 ), there might be no big conformational change or loop reorganization, but involves only local conformational change typically observed in diffusion-controlled association. Taken together, the increase in global flexibility of the complex, clearly indicates the start of unbinding process of the complex. Conclusion: It indicates that such an interruption of electrostatic interactions between the RBD and ACE2, and the increase in global flexibility of the complex, would weaken or block SARS-CoV-2 entry and its subsequent infectivity. We postulate that natural phytochemicals like Tinocordiside could be the viable options for controlling SARS-CoV-2 contagion and its entry into host cells.

Comparative retrospective open-label study of ayurvedic medicines and their combination with allopathic drugs on asymptomatic and mildly-symptomatic COVID-19 patients

“…The main aim of this study was to evaluate the potential of Ayurvedic medicines against COVID-19 infection. The premise for this study has been recognition of epidemic in Ayurveda, mention of treatments for ailments with symptoms resembling those of mild to moderate cases of COVID-19 and reports on anti-viral, immune-modulatory and anti-inflammatory effects of the Ayurvedic medicines being studied or their individual constituents ( Balkrishna et al, 2021b , 2020b , 2020a ; Choudhury et al, 2014 ; Gautam et al, 2009 ; Gupta et al, 2011 ; Hagenlocher et al, 2013 ; Kamala et al, 2018 ; Kanwar and Bhutani, 2010 ; Lee et al, 2019 ; Mahajan et al, 2013 ; Majdalawieh and Carr, 2010 ; Nicolis et al, 2009 ; Pattanayak et al, 2010 ; Pynam and Dharmesh, 2018 ; Rajaram et al, 2018 ; Sinha et al, 2004 ; Tiwari et al, 2017 ; Yadav et al, 2013a ).…”

“…COVID-19 causes viraemia after entering the body and the main clinical manifestations are fever, pharyngalgia, fatigue, diarrhea and other non-specific symptoms. The phytochemicals present in the Ayurvedic medicines mentioned here work at different steps of viraemia, such as, to prevent viral entry ( Balkrishna et al, 2021b , 2020a ), to inhibit viral replication (unpublished data), and to reduce inflammation of the respiratory tract and strengthen immunity ( Balkrishna et al, 2020b ). Observations from a randomized placebo controlled pilot clinical study, that evaluated the effectivity of these medicines on a slightly larger asymptomatic to mildly symptomatic patient pool, upholds our findings from this study ( Devpura et al, 2021 ).…”

“…GG is composed of natural compounds extracted from Tinospora cordifolia (traditionally, known as ‘Giloy’ or ‘Guduchi’ in India). Computational studies have shown that tinocordiside, one of the major phytocompounds, of T. cordifolia docks into the ACE2-RBD complex, and therefore, has the potential to disrupt this critical interaction ( Balkrishna et al, 2020a ). Besides, T. cordifolia is an excellent immunostimulant and effective against various microbial infections ( Sinha et al, 2004 ).…”

Calcio-Herbal Medicine Divya-Swasari-Vati Ameliorates SARS-CoV-2 Spike Protein-Induced Pathological Features and Inflammation in Humanized Zebrafish Model by Moderating IL-6 and TNF-α Cytokines

“… 39 Tinocordiside from Tinospora cordifolia reduced the free binding energy of the host cell ACE-2 and the SARS-CoV-2 spike protein’s Receptor Binding Domain. 40 Other studies identified the potential use of several phyto-compounds such as diterpene, tetranortriterpenoid, phytosterols, and several other FDA approved compounds for efficient blocking of the major protease, Nsp9 replicase, and spike proteins of the SARS-CoV-2 virus. 41 , 42 The various bioactive compounds present in Withania somnifera (Ashwagandha), such as Withanone, Withanoside X, Ashwagandanolide, Dihydrowithaferin A, and Withanolide N were identified as potent inhibitors to the entry of the virus into the host cell using docking experiments in-silico.…”

Phytotherapy for treatment of cytokine storm in COVID­19

“…Among all the screened chemical constituents, molecular docking along with molecular dynamics studies revealed that berberine regulates the M pro protein function and thus inhibits the viral replication [82]. Furthermore, a study by Balkrishna et al demonstrated that one of the phytocompounds of T. cordifolia "Tinocordiside" significantly reduced the electrostatic interaction between ACE2-RBD complexes that leads to enhancement in the flexibility of the complex [83]. Thus, we can postulate that Tinocordiside could be one of the viable options for controlling the SARS-CoV-2 entry into the host cell.…”