Can Javanicins be Potential Inhibitors of SARS-Cov-2 C-3 like Protease? An Evaluation through Molecular Docking Studies

Introduction

Corona viruses belong to the family Coronaviridae and are named such because of spike-like proteins resembling a crown on their surface. Most persons have seasonal attacks of flu caused by this family of viruses, but usually they cause mild fever and cold symptoms, which goes away within a week at the most. However, since 2000, the world has witnessed the emergence of three serious corona virus diseases, SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and the latest, namely SARS-CoV-2 otherwise designated by the World Health Organization (WHO) as COVID-19. Among the three, COVID-19 has proved to be the most serious for two major reasons. Since its outbreak in late December in 2019, till as of June 9, 2020 the virus has infected 7,237,929 people throughout practically every country of the world and caused deaths of 409,630 persons. Thus far, despite the best efforts of scientists, any vaccine or drug against COVID-19 is yet to be discovered. The extreme contagiousness of the virus along with the occurrences of repeat spikes in infections has caused serious dents in the world economy and severe unemployment in many countries because of the necessity of keeping people and families isolated from each other through lockdowns and quarantines.

A number of synthetic drugs originally intended for other uses like use against other viruses or even malaria has been tested against COVID-19 both with COVID patients as well as in silico studies. Three such synthetic drugs have shown promise in molecular docking studies (methisazone, CGP42112A, and ABT450) [1] but nothing further has been reported regarding clinical trials of these compounds. The repeated failures of existing allopathic drugs, and absence of other viable allopathic drugs or vaccines is turning the attention of scientists to the plant kingdom and traditional medicinal systems, which has always been a major source of discovery of many important allopathic medicines [2].

A 3D-homology model of 3CLpro was screened against a medical plant library containing 32,297 potential antiviral phytochemicals/traditional Chinese medicinal compounds and nine hits were obtained in this molecular docking approach [3]. Baicalein, isorhamnetin, kaempferol, luteolin, and naringenin were among the 10 plant-based compounds postulated to be effective against COVID-19 on the basis of molecular docking studies with COVID-19 proteins like the 3CLpro [4]. Four traditional Chinese medicines, namely HuoxiangZhengqi, LianghuaQingwen, ShuefengJidue, and XueBijing have shown promising results in the treatment of COVID-19 [5].

Picrasma javanica Blume belongs to the Simaroubaceae family and can be found in Indonesia, India and other tropical countries. Since the plant has indigenous uses as an antiviral [6], it was of interest to evaluate through molecular docking studies whether phytochemicals reported from the plant can bind to 3CLpro of SARS-CoV-2. For a comparative analysis we also assessed through molecular docking studies whether the same phytochemicals of Picrasma javanica can bind to SARS 3C-like protease. For purposes of this paper we selected 12 quassinoid compounds from this plant, namely javanicins B, E-K, M, N, P and Q. Javanicins have a novel C-20 structure and belong to des-4-methylated picrasane type quassinoids. Various javanicins have been isolated from leaves, roots and bark of Picrasma javanica. Javanicins E, F, G and M were isolated from the barks of the same plant [7]. Javanicin N was isolated from the wood of Picrasma javanica, and javanicins P and Q from leaves of the same plant [8]. Javanicin B was isolated from the bark of the plant [9]. Javanicins K, L, O, R, S and T were isolated from leaves and stems of the same plant [10]. Javanicins H, I and J were isolated from leaves of the same plant [11].

A number of phytochemicals have been screened thus far through molecular docking analysis of binding of the compounds to the C3-like protease of COVID-19. Some phytochemicals (belonging mostly to the flavonoid group) have shown promise but has not resulted in practical use as anti-COVID drugs. Yet molecular docking remains a powerful tool for initial screening of possible anti-COVID compounds as well as other types of antiviral compounds. In this study, we for the first time report molecular docking screening analysis of javanicins from Picrasma javanica against 3CLpro of SARS-CoV-2 and SARS.

Results and Discussion

The predicted binding affinities of the javanicins with C3-like protease of SARS and SARS-CoV-2 are shown in Table 1. Javanicin G showed the most affinity for SARS-CoV-2 3CLpro with a binding energy of -8.2kcal/mol. Two other javanicins, namely javanicins N and K also demonstrated high binding energies of -7.9 and -7.8 kcal/mol, respectively. Javanicin E gave the lowest binding energy of -6.6 kcal/mol followed by javanicin P with a binding energy of -6.7 kcal/ mol. It is to be noted that javanicins G, K and N also gave high binding energies with the C-3 like protease of SARS. Interestingly, unlike the C-3 like protease of SARS-CoV-2, all twelve javanicins showed high binding affinities with C-3 like protease of SARS, indicating that these classes of compounds may be potentially effective therapeutic agents against both SARS and SARS-CoV-2.

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The binding of javanicin G with the 3C-like protease of SARS-CoV-2 is shown in Figure 2. As mentioned earlier, the interacting residues of an inhibitor N3 with the protease amino acids has been shown to be His41, Met49, Phe140, Leu141, Asn142, Gly143, His163, His164, Glu166, Leu167, Pro168, Gln189, Thr190, and Ala191. The active residues of SARS-CoV-2 3C-like protease have been shown to be His41 and Cys145.

2D ligand interaction diagram of representative docked poses of Javanicin G (Figure 2) shows that Javanicin G establishes interactions with several of the residues (Met165, Glu166, His41, Met49) of the protease that are known to interact with known covalent and non-covalent inhibitors hitherto published. But most of these interactions seem to involve various parts of the benzdioxole ester side group attached to the main quassin-type polycyclic scaffold. Javanicin G and other quassinoids do not appear to have any strong electrophilic group to form any covalent adduct with the active site Cys. Therefore these molecules are unlikely to act covalently. Excluding Javanicin N, the predicted binding affinities of the javanicins were better against the SARS protease than the SARS-2-COV-2 protease.

Conclusion

In future, Javanicin G and ideally most of the other javanicins should be tested for physical interaction with the proteases and any possible inhibition of the function of these proteases.

Acknowledgement

The authors are grateful to Professor Dr. Abdul Hamid, CEO, Agrarian Research Foundation for support.