Based on the experiences on SARSCoV, MERS-CoV, Ebola virus, malaria, and influenza, a few antiviral drugs are thought to effectively stop the SARS-CoV-2 spread [17,18]. Oseltamivir, Peramivir, Zanamivir, Ganciclovir, Acyclovir, and Methylprednisolone are already reported to be almost ineffective against SARS-CoV-2. Some other antiviral drugs like Umifenovir, Galidesivir, Ribavirin, Triazavirin, Ritonavir, Nitazoxanide, Favipiravir, Lopinavir, Ritonavir, Nafamostat, Darunavir and Remdesivir, and an antimalarial drug Chloroquine, have been used separately or in combination to treat COVID-19 patients. Though some effects and even recovery is reported for each of those treatment plans, none are found promising except a combination of Remdesivir and Chloroquine [17-23]. Viral infections can suppress host immunity, and previous reports show that application of immune-boosters like interferons along with an antiviral drug can help survival and prognosis [20,21,24]. Therefore scientists are working on combinatorial approaches using different drugs like Remdisivir and/or Chloroquine along with immune-boosters. Recently, a blocker for ACE2 or TMPRSS2 is being tried to prevent the viral entry in to the host cell. Interestingly, WHO has announced a combinatorial approach using Remdisivir, Chloroquine, a blocker as said above, and an immune-booster as said above [3,14,17,18]. We have screened a lot of candidate molecules by checking the binding properties of those with different essential viral proteins separately. The possible efficacy of any candidate drug helped us suggest a possible combinatorial treatment plan to be implemented.
Remdesivir, Galidesivir, and Pirodavir are the choice of antiviral drugs
After initial screening, we have finalized a set of six antiviral drug candidates for detailed study to propose the combinatorial therapy (Table 1). Receptor-ligand interactions are analysed taking the drugs and the important viral proteins individually. We have chosen the drugs which show at least one interaction with at least one viral protein with at least -0.7 kcal/mol of binding energy (Table 1, Supplementary table 1).
Remdesivir has already proved its efficacy against SARS-CoV-2. In our screening methods, we also have found that this drug can interact with a variety of viral proteins. Two other drugs, Galidesivir and Pirodavir, also seem promising as they can target more than one viral protein (Figure 2, Table 1, Supplementary table 1). Interestingly, none of these can interact effectively with the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein; thereby they cannot prevent the entry of the virus into the host cell (Supplementary figures 1,2).
Some other drugs may serve as the promising candidates for using in combination with the antivirals
A Chloroquine derivative, Hydroxychloroquine, is being widely used as a promising treatment strategy for COVID-19 [3,26,27]. Though we have found Chloroquine to interact with some SARS-CoV-2 proteins (Figure 3a), it should be noted that Hydroxychloroquine can reduce both innate and adaptive immune responses significantly by suppressing Toll-like receptor signalling (TLR) pathways [28-30]. Therefore the use of Chloroquine molecule in must be monitored carefully, and we exclude this known molecule from our proposals.
We have searched for a few FDA- (the U.S. Food and Drug Administration) approved drugs and/or chemical which might prove them promising for the management of COVID-19 (Table 1) [31]. A recent report has already suggested Ivermectin for treating COVID-19, though the results are not confirmed in humans [26,32]. Looking on Chloroquine, we searched for other antimalarial drugs approved by FDA. We found that many of those show promising interactions with viral proteins (Figure 3b). Depending upon such possible interactions and reported side effects, we inferred that Proguanil, Artesunate, and Mefloquine may serve as candidates for the proposed combinatorial therapy. Artementher and Quinine may also be tested, but they show less favourable interactions (Figure 3b,c,d; Table 1, Supplementary figure 2).). Though Amodiaquine belongs to the WHO safe drug list, we have excluded that for its rare but serious side effects and interactions with certain genotype [32].
Host cell entry of SARS-CoV-2 should be prevented
None of the above chosen antiviral and antiparasitic drugs can interact with the Spike-RBD and RdRp. Therefore, they cannot prevent the viral entry as well as its replication. We have concentrated our next choice on any blocker which can prevent viral entry (Supplementary table 2) [14,33]. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to generate angiotensin II and this binds angiotensin II type 1 receptor (AGTR1) which constricts blood vessels, thereby elevates blood pressure. On the other hand, ACE-2 inactivates angiotensin II and helps vasodilation. Inhibitors to AGTR1, like Losartan and Olmesartan, are reported to increase ACE2 and thus vasodilation [33,34]. Hypothetically, any blocker for ACE-2 might prevent host cell entry and thereby might prevent COVID-19 [35]. But the role of ACE-2 is essential for the survival of the host and it is already reported that reduced ACE-2 can lead to lung injury, arrhythmia and cardiac failure. In addition ACE-2 is found in a variety of organs and SARS-CoV-2 attacks those organs also resulting in low ACE-2 [14,36,37]. Therefore, the blockers against ACE or AGTR1 might be helpful as they can increase ACE-2 and might prevent pneumonia seen in COVID-19, as suggested by some [38,39].
A recent report also suggests for an inhibitor for TMPRSS2, camostat mesylate, to inhibit the priming of spike glycoprotein and subsequent entry into the host cell [14]. Previously another inhibitor for TMPRSS2, Nafamostat, has been suggested for treating MERS-CoV and Ebola infections [39]. It is to be noted that SARS-CoV-2 is much similar to MERS-CoV and therefore, Nafamostat may also serve as a potential candidate for preventing SARS-CoV-2 entry into the host-cells.
Vitamins C, D, B6 and Zink can play as immuneboosters to fight COVID-19
Host immunity plays the most important role for establishment and prognosis of any infection and supplements to boost immunity may be given to COVID-19 patients as suggested by some [40,41]. A healthy lifestyle and food helps immune system the most. But majority of the patients are not much immunocompetent due to reasons like unhealthy lifestyle, ageing, and poor socio-economic conditions. Therefore some approved supplements may be added to their treatment plan to fight COVID-19 successfully. Based on cited literature, we have chosen a few such candidates which might help treatment (Supplementary table 3) [40-43]. As discussed in other reports, along with these, interferon(s) may be given to the patients as a support to the drugs [24].
A, B, C, and D are the choices of treatment plans
After detailed study, as discussed above, we have finalized a set of four treatment plans for the proper and effective management of COVID-19 (Figure 4; Table 2, Supplementary table 4). Possible adverse interaction(s) of each of these drugs has been searched from authentic public databases [44,45]. Any possible side effect(s) are also listed in the plans.