Computational screening for investigating the synergistic regulatory potential of drugs and phytochemicals in combination with 2-deoxy-D-glucose against SARS-CoV-2

Abstract

COVID-19 disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was declared a global pandemic by the World Health Organization (WHO) in March 2020. Since then, the SARS-CoV-2 virus has impacted millions of lives worldwide. Various preclinical and clinical trials on the treatment of COVID-19 disease have revealed that the drugs that work in combination are more likely to reduce reinfection and multi-organ failure. Considering the combination drug therapy, herein, we performed a systematic computational study starting with the formation of sixty-two combinations of drugs and phytochemicals with 2-deoxy-D-glucose (2-DG). The top nineteen combinations resulting from Drug-Drug Interaction (DDI) analysis were selected for individual and multiple-ligand-simultaneous docking (MLSD) study with a host target Serine Protease (TMPRSS2; PDB ID: 7MEQ) and two viral targets, Main Protease (3CLpro; PDB ID: 6LU7) and Uridylate-Specific Endoribonuclease (NSP15; PDB ID: 6VWW). We found that the resulting drugs and phytochemicals in combination with 2-DG shows better binding than the individual compounds. We performed the re-docking of the top three drug combinations by utilizing the polypharmacology approach to validate the binding patterns of drug combinations with multiple targets for verifying the best drug combinatorial output obtained by blind docking. A strong binding affinity pattern was observed for 2-DG + Ruxolitinib (NIH-recommended drug), 2-DG + Telmisartan (phase 4 clinical trial drug), and 2-DG + Punicalagin (phytochemical) for all the selected targets. Additionally, we conducted multiple-ligand-simultaneous molecular dynamics (MLS-MD) simulations on the selected targets with the 2-DG + Ruxolitinib combination. The MLS-MD analysis of the drug combinations shows that stabilization of the interaction complexes could have significant inhibition potential against SARS CoV-2. This study provides an insight into developing drug combinations utilizing integrated computational approaches to uncover their potential in synergistic drug therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02049-0.

2-Deoxy-D-Glucose: A Novel Pharmacological Agent for Killing Hypoxic Tumor Cells, Oxygen Dependence-Lowering in Covid-19, and Other Pharmacological Activities

“…Drug-drug interactions (DDI) and synergistic regulatory potential have been investigated in a report describing a molecular coupling and simultaneous molecular dynamics simulation of multiligands to study the combined efect of 2-DG with other 62 selected drugs and phytochemicals. In terms of binding energy, the combination of 2-DG with Ruxolitinib, Telmisartan, and Punicalagin was superior to that of the selected individual compound [114].…”

Anti-COVID-19 Potential of Ellagic Acid and Polyphenols of Punica granatum L.

“…The cleavage site recognized by the protease appears in proteins involved in human innate immunity and may interfere with the immune response to viral infection [45]. Due to the apparent suitability of 3CL pro for drug development, a vast range of studies have included plant polyphenol-3CL pro docking, including PUN, punicalin, corilagin, chebulagic acid and geraniin, as well as EA and urolithins [93,104,[106][107][108][109][110][111][112][113][114]. The catalytic dyad of 3CL pro is composed of H41 and C145, and in silico docking showed that EA and its precursors form H-bonds with the catalytic C145 residue [104,[106][107][108]114].…”

“…The two viral proteins nsp9 and nsp10 (methyltransferase) interact with NFκB repressing factor (NKRF) and may interfere with NFκB transcription activity, for which NKRF competes [46]. Nsp15 (endonuclease) and PUN were identified as interacting in silico [110]. A more extensive screen identified punicalin as the lowest binding energy partner for RdRp (nsp12, RNA-dependent RNA polymerase), as well as for nsp9 and PL pro (nsp3, papain-like protease) [1].…”

“…The active site amino acids in TMPRSS2 (Q276, E299, K300, P301, K340, K342, E389, K390, L419, S441, Q438, and W461) and the catalytic triad H296, D345 and S441 interact with the SARS-CoV2 S-protein. They also appear to be recognized by pedunculagin and PUN and by bromhexine and serine protease inhibitors, such as camostat, as agents that inhibit TMPRSS2 and have been considered in COVID-19 treatment [110,117,119]. Camostat and nafamostat act by acetylating the S441 residue, which is also recognized by the ETs [118].…”

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study

“…3 Drug combination therapy could exhibit synergistic efficacy and reduce resistance. 4,5 Combination therapy can also minimize harmful side effects by lowering the drug doses 6,7 (Figure 1). Pyrazoline derivatives are heterocyclic compounds that have been reported to have promising pharmacological activities against cancer cells, such as cell division inhibition and apoptosis induction.…”