Computational studies by molecular docking of some antiviral drugs with COVID - 19 receptors are an approach to medication for COVID - 19

: The COVID - 19 outbreak is a matter of concern worldwide due to unavailability of promising treatment comprising medication or vaccination till date. The dis - covery of antiviral drug is of immense importance in the existing spread of novel coronavirus. The goal of the pre - sent study was to evolve an opposite antiviral drug against the novel COVID - 19 virus. A directly succeeding perspective would be to use the prevailing in ﬂ uential drugs from several antimicrobial and chemotherapeutic agents. The encouraging approach is to identify pro - mising drug molecules and compounds through virtual screening via molecular docking of FDA - approved drugs and some previously synthesized pyridone and coumarin derivatives for probable therapeutic outcome. In this con - ceptual milieu, an e ﬀ ort has been made to propose a com - putational in silico relationship among FDA - approved drugs and coronavirus - associated receptors and proteins. The study results were evaluated on the basis of a dock score by using molecular operating environment. Out of 15 compounds screened, the compounds with the best docking scores toward their targets was 3d . Therefore, compound 3d deserves further investigations and clinical trials as a possible therapeutic inhibitor of the COVID - 19 caused by the novel SARS - CoV - 2.

It is the energy released when a drug molecule accompanied by a target, resulting in a lowering of the overall energy of the complex Docking score It is a procedure to quantify the predictive capability of a docking protocol. While scoring functions are mathematical functions which used to approximately predict the binding affinity between two molecules after they have been docked PDB protein data bank MOE Molecular operating environment

Introduction
Docking process includes both of prediction of ligand conformation and of orientation which means posing within a targeted binding site. The docking studies have two important aims, namely, are accurate structural modeling and correct prediction of activity. Mankind has formerly witnessed the outburst of numerous deadly pathogens such as Zika, Ebola, the Middle East respiratory syndrome (MERS) coronavirus, severe acute respiratory syndrome (SARS) coronavirus, and, currently, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1][2][3][4][5]. The novel COVID-19 pandemic is an ongoing global concern which is also known as the severe acute respiratory syndrome coronavirus spread worldwide [6,7]. The COVID-19 is extremely contagious and potentially fatal disease that can cause mild to severe respiratory tract infections. The COVID-19 outbreak has caused economic and social disruptions globally [8,9]. The contagious nature of COVID-19 infection led to the isolation of patients who were subsequently given various treatments [10][11][12]. The most problematic factor of the pandemic is the rate of transmission. Consequently, the numbers of patients are increasing day by day still with no treatment [13]. Undoubtedly, developing a new drug or vaccine typically takes a long time as it should be intensively tested and ensured to be safe through clinical trials prior to approval for human subjects [14,15]. Although many antiviral drugs and vaccines are undergoing clinical trials against COVID-19, none of them proved their safety and efficacy [16,17]. Currently the COVID-19 is a global pandemic and the situation is not under control [18]. Numerous scientists and researchers are working worldwide to find an efficient means to prevent the pandemic. Due to the unavailability of any approved antiviral drug for COVID-19 treatment, one of the best and fast way to find the antagonist of COVID-19 is through clinically screening the currently available drugs. Hence, repurposing of the clinically available drugs and the available antimicrobials in literature seems to be a faster way to get the target drug [19].
2-pyridone compounds were also shown to be potent nonnucleoside HBV inhibitors [31]. Coumarin is a natural compound and is a potential drug candidate owing to its properties of stability, solubility, and low toxicity. There are numerous evidences showing its inhibitory role against infection of various viruses such as HIV, influenza, enterovirus 71, and coxsackievirus A16 [32][33][34][35].
Virtual screening is a prevalent modeling tool broadly employed in structure-based drug design [36][37][38][39][40]. It is an imperative means to predict the binding affinity, type of interaction, and the suitable receptor-binding sites among the drug and corresponding receptor by using, for example, scoring functions. In the rational drug design and explicate fundamental biochemical processes, elucidating the binding behavior has an important role [41,42]. In the present study, molecular docking was performed on previously synthesized compounds and drugs mentioned in the clinical protocol of WHO for the treatment of COVID-19. The molecular operating environment (MOE) 2018 modeling program was utilized to predict the binding sites and docking score.

Molecular docking method
All docking studies were performed using the MOE program 2018. Structure optimization of the compounds and all drugs that were used as inhibitor agents to COVID-19 was performed by Gaussian 09 program package [45] using the density functional theory with B3LYP [46] and the 6-311++G(d,p) basis sets. The crystal structure of target protein was retrieved from the Protein Data Bank (http://www.rcsb.org/pdb/). The Docking score in MOE software was utilizing and accompanied by the five poses for output refinement for final binding poses. Rootmean-square deviation (RMSD) of the compound position compared to the docking, the pose was used in ranking. Both RMSD and the mode of interaction of the native ligand within the structure of the receptor were used as the standard docked model [47][48][49][50][51][52][53]. Coronavirus has glycoprotein spikes arranged like a crown. Coronavirus infects its host in three stages. The first stage involves the virus infecting its host by attaching the transmembrane spike-conjugated protein to host through angiotensin-converting protein 2 (ACE 2) within the host so a fancy is formed between S-glycoprotein with ACE-2 with the assistance of transmembrane protease, aminoalkanoic acid 2 (TMPRSS2), produced by host cells. The consequent stage is the replication stage wherein the ribonucleic acid-dependent RNA polymerase (RdRp) is exploited. Coronaviruses are ribonucleic acid viruses that use host cells to replicate. Coronavirus uses RdRp to form new ribonucleic acid copies. The last stage is the maturation stage of virus replication within the host cell by exploiting proteases akin to 3C-like protease (3CLpro) and papain-like protease (PLpro). Some medication is proverbial to be able to inhibit these three processes as well as Arbidol as ACE2 inhibitors, camostat mesylate as TMPRSS2 inhibitors, remdesivir and antiviral agent as RdRp inhibitors, and lopinavir and protease inhibitor as protease inhibitors. Chloroquine, lopinavir, protease inhibitor, and remdesivir are antimicrobials that contain a potential activity against SARS-CoV 2. The target proteins, which are the targets of inhibition, are ACE2, TMPRSS 2, RdRP, 3CLpro, and PLpro [54][55][56][57].
Ethical approval: The conducted research is not related to either human or animal use.

Result and discussion
In silico methods and computational molecular docking studies are effective tools, which are broadly utilized to interpret the molecular aspects of ligand-protein interactions during drug discovery against various prior fatal and emerging diseases including SARS coronavirus [41,42]. In the present study, the virtual screening of numerous previously synthesized 2-pyridone derivatives (1a-e) and acetyl coumarin derivatives (2a-e, 3a-e) [43,44], which were already reported to have anticancer and antibacterial activities along with the drugs used in WHO COVID-19 treatment protocol, was performed against the human angiotensin-converting enzyme (PDB code = 1O86), SARS-CoV-main peptidase (PDB code = 2GTB), serine protease hepsin (PDB code = 5CE1), human coronavirus papainlike proteases (PDB code = 4OW0), and SARS-Coronavirus NSP12 (PDB code = 6NUR) to discover the most predicated drug-ligand interactions. The obtained parameters contain the docking scores, binding efficiency of ligand, and hydrogen bonding interactions. The results of the molecular docking studies of pyridone and coumarin series against the aforementioned proteins were compared with that obtained using different drugs mentioned in the WHO's clinical protocol of COVID-19 treatment such as Umifenovir, chloroquine, camostat, remdesivir, ribavirin, and lopinavir. The topmost compounds were carefully chosen and are presented in Tables 1-6 and Figures 1-5. The study results of the binding score energy of pyridone series represented in Table 2 for compounds 1a-e are −6.37, −6.54, −6.68, −7.03, and −6.21, respectively. By comparing these scores, one can find that compound 1d has higher binding score energy than ribavirin and it is near to the binding score energy values of chloroquine. Also compounds 1a-c are most active compared to ribavirin while this series is of less activity toward 1O86 as compared to references Umifenovir, chloroquine, camostat, remdesivir, and lopinavir. This means only compound 1d is the most welcome compound in this series toward 1O86.
The same series was investigated for 2GTB protein, and the binding score energy is represented in Table 4. Compounds 1a-e showed the binding score energy −6.39, −6.23, −7.21, −6.98, and −6.64, respectively, and this series exhibited higher activity than ribavirin. Compound 1c represented a good activity near the binding score energy value of Umifenovir and camostat values, and higher than chloroquine binding score energy values. By examination of this series for 4OW0 in Table 6, it is noticed that they are more active than ribavirin only.
The study results of the binding score energy of 5CE1 protein shown in Table 8 indicated that the series is more active than ribavirin; while the binding score energy values of compounds 1c, 1d are near to camostat and Umifenovir values. The study results of this series for 6NUR protein is shown in Table 10, demonstrating higher binding score energy values than Umifenovir, chloroquine, and ribavirin.
The interaction between the compounds and the chosen standard antiviral with 1O86 protein is presented in Table 1. Compound 1a is bonded to Lys 368 by Hacceptor, compound 1b with GLN281 also by H-acceptor, and compound 1d is bonded to ARG 124 by H-acceptor; while compounds 1c and 1e as well chloroquine and lopinavir showed no measurable interaction with 1O86 protein.
Similarly, the interaction between the compounds and the chosen standard antivirals with 2GTB protein is given in Table 3, showing that compound 1a bonded to the receptors at Gly143 like Umifenovir, remdesivir, and ribavirin. While chloroquine has no measurable interaction. The interaction between the investigated compounds and the chosen standard antiviral with 4OW0 protein in Table 5  The interactions between the compounds and the chosen standard antiviral with 5CE1 protein is illustrated in Table 7. The receptor interacted with the ribavirin at GLY 380(A), and the results showed that compounds 1a, 1b, and 1d are bonded to the receptor from the same position and all of them are connected by H-acceptor. Compound 1b is bonded to the receptor at CYS 381(A), by H-donor like ribavirin and camostat, while compounds 1a, 1b, and 1c are bonded to the receptor by pi-H at position CYS 349(A) like chloroquine, remdesivir, and lopinavir.
The interactions between the compounds and the chosen standard antiviral with 6NUR protein are represented in Table 9. As a whole, compound 1c has no measurable interaction. Compounds 1a and 1b are bonded to the receptor from ARG 624(A), by H-acceptor like Umifenovir, chloroquine, ribavirin, and lopinavir.
Compounds 1a, 1b, and 1d represented interactions with the receptor at ARG 555(A), like lopinavir although they are interacted by H-donor, and lopinavir is bonded by pi-cation to the receptor. Compound 1a interacts with the receptor at SER 682(A), by pi-H like remdesivir, while camostat is bonded to the same position but by H-acceptor interaction. Camostat is also bonded to the receptor at ARG 553 by pi-H while Umifenovir is bonded by pi-cation, and compound 1b is bonded to the same receptor, but compounds 1d and 1e are bonded by Hacceptor.
The study results of the coumarin series for 1O86 protein and the binding score energy are represented in Table 2. From the data obtained in Table 1, it is observed that compounds 2a, 2b, 2c, 2d, and 2e have binding score energy values of −6.21, −6.35, −6.69, −6.84, and −6.63, respectively. It is clear that all of them have higher docking score than ribavirin. Compounds 3a, 3b, 3c, 3d, and 3e have binding score energy values of −6.08, −6.48, −6.78, −7.08, and −6.63 respectively, and it is noticed that all of them have higher docking score than ribavirin while only compound 3d's score was near chloroquine. Hence, it is concluded that compound 3d is the most welcomed compound in this series for 1O86.
The same series was examined for 2GTB protein and the binding score energy is represented in Table 4. Compounds 2a, 2b, 2c, 2d, and, 2e have binding score energy values of −6.16, −6.16, −6.29, −7.17, and −6.78 respectively, and it is apparent that all of them scored higher than ribavirin. While compound 2d has binding score     The results of the binding score energy of the same series for 4OW0 protein are represented in Table 6. Compounds 2a, 2b, 2c, 2d, and 2e have −6.81, −6.96, −6.76, −7.45, and −7.12 respectively, and all of them scored higher than ribavirin. Compounds 3a, 3b, 3c, 3d, and 3e have binding score energy values −7.43, −7.34, −7.34, −8.22, and −7.34, respectively. It disclosed that all of them have higher values than ribavirin. Moreover, compound 3d has higher binding score than chloroquine. Therefore, compound 3d appeared as the most active one for 4OW0 protein.
The binding score energy results of same series toward 5CE1 protein given in Table 8 exhibited that compounds 2a, 2b, 2c, 2d, and 2e have binding score energy values of −6.46, −6.5, −6.74, −7.16, and −6.93, respectively, and compounds 3a, 3b, 3c, 3d, and 3e represented docking score of −6.72, −6.77, −6.69, −7.54, and −7, respectively. All of the docking scores of coumarin series are higher than the docking score for ribavirin, although compounds 3d and 3e afforded higher score than Umifenovir; in addition, compound 3d scored higher than camostat and chloroquine. The docking score of the same series for 6NUR protein displayed in Table 10 showed that compounds 2a, 2b, 2c, 2d, and 2e have binding score energy values of −5.94, −6.06, −6.16, −6.86, and −6.57, respectively, and compounds 3a, 3b, 3c, 3d, and 3e represent docking score of −6, −6.17, −6.34, −7.12, and −6.69. All the compounds in this series are showing binding score higher than ribavirin, and compounds 3d and 3e exhibit higher docking score than chloroquine and Umifenovir. Conclusively, the study results reveal that compound 3d emerges as the most effective compound toward all the proteins examined. Although 3d has no measurable interactions with the receptors of 1O86 as noticed in Table 1, it actually has a significant docking score and its value is near to chloroquine as shown in Table 2. While 3d is bonded to the receptors of 2GTB, at N-Gly 143(A) by H-acceptor, which seems to be like remdesivir, ribavirin, and Umifenovir; and all of them are also bonded by hydrogen acceptor ( Table 3). The docking score of 3d proved that it has higher activity than Umifenovir, chloroquine, camostat, and ribavirin ( Table 4).
It is noticed the interaction between compound 3d and protein WO40 happens at the same fragment NZ LYS 158 like remdesivir by pi-cation, and at the fragment NH1 ARG 167-B like ribavirin ( Table 6); and it has high docking score values when compared to chloroquine and ribavirin.
Compound 3d interacted with 5CE1 at fragments CYS 188(A) by H-donor and GLY 52(A) by H-acceptor, although none of the tested references showed any interactions at these fragments but the tested compound 3d has a docking score of −7.54, which is higher than that of Umifenovir, chloroquine, camostat, and ribavirin (Tables 7 and 8).
The binding site interaction between 3d and 6NUR happens at ARG 553(A) like camostat and SER 682(A) like remdesivir, and all of them are bonded by pi-H. The docking score of compounds 3d is −7.12, which is higher than Umifenovir, chloroquine, and ribavirin (Tables 9 and 10).          The purpose of this study is to gauge the binding affinity of the active compounds within the target protein that plays a task in the method of virus entry in host cells, virus replication, and therefore the in silico process of virus maturation in host cells. Of the 15 compounds of two prepared series of 2-pyridone derivatives and coumarin derivatives, It has been thought that compound no. 3d was the foremost profit one. Compound 3d showed higher activities toward 2GTB, 4OW0, 5CEI, and 6NUR over Umifenovir, chloroquine, camostat, ribavirin, and generally remdesivir. Hopefully, this analysis will contribute to the discovery of a drug for the COVID-19 antiviral. Data availability statement: The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.