The Pharmaceuticals Using for COVID-19 Patients and in Silico Natural Product Studies about COVID-19

The COVID-19 pandemic without a doubt will be regarded the biggest epidemic which is still going on to impact the whole world in the humanity history. That’s why it is imperative to discover new therapeutic agents and vaccines by the scientific world. review especially includes the studies and reviews about protocols used in cure COVID-19, also the papers about in silico researches on phytochemical compounds and the other marketed drugs. The aim of the review to summarize the antiviral drugs experienced in COVID-19 cure during the first peak of the pandemic; compile and inform the in silico studies focused on the plant sourced compounds and repurposed drugs. The review will generate a guiding source to further in vitro and in vivo research in the proposes that Withanoside V in Ashwagandha may be serve as a possible inhibitor con Mpro of SARS-CoV-2 to fight COVID-19 and may own an antiviral activity on nCoV [156]. In the Chikhale et. al.’s manuscript, molecular docking investigations offered Withanoside X and Quercetin glucoside from W. somnifera possess desirable interactions at the binding site of chosen proteins, that is, 6W01 and 6M0J. The topmost phytochemicals from docking analyses, submitted to 100ns molecular dynamics (MD) offered Withanoside X with the greatest binding free energy (DGbind 1⁄4 89.42kcal/ mol) as the most encouraging inhibitor. Along MD analyses, the compound adjusts its conformation for perfect fitting with the receptor active pocket confirming the powerful binding affinity.


Introduction
In these bizarre moments, the Coronavirus infection 2019 (COVID-19) pandemic has had a serious impact globally. Most countries have enforced strict 'lock-down', and social distancing and isolation of the old and vulnerable are considered [1].  is lead to SARS-CoV-2, which is a positive-sense single-stranded RNA virus. The infection is frequently perplexed by a obvious inflammatory response, which, in order, can beget multiorgan malfunction, respiratory collapse, and death [2]. There is no accepted practical cure for SARS-CoV-2 epidemic, showing an acute and crucial required for novel drugs or vaccines [3,4]. SARS-CoV-2 is commonly less pathogenic than SARS-CoV, much less pathogenic than the Middle East respiratory syndrome MERS-CoV, but more pathogenic than practically powerless HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. The announced case-fatality rate of COVID-19 is %3% and is so rather low as compared with SARS 30% (Table 1). Nonetheless, the transmission rate (TR) (number of newly infected people per infected person) of 2.5 to 3 is high and clarifies the danger of the current pandemic. For comparison, the TR of the yearly typical cold is less than 1.4 [5]. In December 2019, an abnormal viral pneumonia induce to a novel coronavirus was diagnosed in Wuhan, China [6]. Within months, the disease, later

c. Ribavirin
Ribavirin is a purine nucleoside derivative with a extensivespectrum antiviral power [29]. It is used primarily to heal

g. Chloroquine Phosphate
Chloroquine phosphate (ResochinTM) and its derivative hydroxychloroquine (QuensylTM, PlaquenilTM, HydroquinTM, DolquineTM, QuinoricTM) have been practiced for ten years for the prophylaxis and healing of malaria and for the cure of chronic Q fever and various autoimmune illnesses [69] and have newly been indicated as promising broad-spectrum antiviral medicine [38,70,71]. Chloroquine phosphate is an antimalarial medicine that has been on the market for many years, and it also has a promising broad-spectrum antiviral effect [72,73]

h. Hydroxychloroquine
As a derivative of chloroquine, hydroxychloroquine has akin potency and few side effects. Stand on its typical features of immunomodulation, antithrombotic action, and augmented inflammation, hydroxychloroquine has been practiced in the clinical cure of systemic lupus erythematosus [86]. Hydroxychloroquine has been presented to have anti-SARS-CoV activity in vitro [87], and it is clinically harmless than chloroquine [88,89] Nevertheles, as not all cases entered the research at the same stage of the ailment, it is hard to evaluate whether the clearance in viral RNA was due to the cure or due to the immune system of the patient.
Besides, the mixture of chloroquine and azithromycin is related with fierce QT prolongation and should so be considered with carefulness. Before chloroquine can be believed safe and powerful as a medication for COVID-19, more researches are required [85].

i. Ivermectin
Ivermectin has been investigated onwards 1946 against avid diphtheria. It was regarded as an mysterious multifaceted 'wonder' compound in 2017 [92]. More currently it has also been applied (as already accepted by the FDA) as an anti-parasitic against scabies and evenly against HIV, Zika, Dengue, West Nile, and Influenza viruses [93]. Its mechanism of action draws in the dissociation of the preformed IMPα/β1 heterodimer, in charge for the nuclear transport of loads of viral proteins [94]. j.

l. Azitromycin
Researchers suggest valuable impacts of azithromycin in decreasing viral load of hospitalized sufferers, likely intervening with ligand/CD147 receptor interactions; nonetheless, its possible impact on SARS-CoV-2 infiltration has not yet been appraised. were also prevalent ligands, binding powerfully to both proteins.
A recent study has displayed ameliorating action of Neem extract on propagation and pathophysiology of another representative of the coronavirus family [104], augment the potential of these compounds as potential therapeutic preferences.
The main protease of SARS-CoV-2 is one of the significant aims Hence, the Sinha and co-workers' study was attempted to evaluate and appraise the efectiveness of various Saikosaponins against various sets of SARS-CoV-2 binding protein via computational molecular docking simulations [106].
From the binding energy and interaction researchs, the Saikosaponins U and V displayed the perfect affinity towards both the proteins proposing them to be future investigation compound as they identify the ambition interaction with NSP15, which is at the bottom of duplication of RNA and also with 2019-nCoV spike glycoprotein which control the binding to ACE2 [106]. Saikosaponin ideal property for oral and intestinal absorption and is able to be absorbed sub-lingual as well. Through water solubility characteristics predicted the drug is free soluble [107]. In the Fakhar and co-workesrs' study, the nominee anthocyanin-derived molecules from PubChem library were filtered seeing antiviral properties of anthocyanins. The structure-based pharmacophore modeling was deepened standed on the co-crystallized structure of the enzyme with its biological effective inhibitor. The spawned hypotheses were practiced for virtual screening-based PHASE Screen  [111][112]  2GTB peptidase indicate that these compounds are promising nominee for planning novel medicines to combat Covid-19 [117].
Cefuroxime also as a high-ranked possible inhibitor medicine against SARS-CoV-2 proteins. Six researches were described.
These studies showed Cefuroxime as a possible inhibitor of 3 key SARS-CoV-2 proteins; main protease, RNA dependent RNA polymerase, and ACE2-Spike complex [118]. Galvez  while Cefuroxime had an index value of 3.9 [118].
Almeciga-Diaz and colleagues [121] utilized a proprietary algorithm [122] to evaluate a subgroup of ZINC database for medicine that could connect to the active hole of Mpro. They detected a greatly strong correlation (R2 1⁄4 0.89) between the binding energy and noted IC50 of these inhibitors. Thereupon, they anticipated IC50 stand on binding energy. From scanning of over 11,000 medicines, they found 10 possible inhibitor medicines, containing Cefuroxime, that owned smaller binding energy than the formerly mentioned inhibitors. Cefuroxime listed 8th and was concluded to attach with affinity energy of -9.2kcal/mol with an IC50 of 2.09mM [118]. Koulgi and co-workers [123] applying both a "direct docking" and an "ensemble docking" approach. The direct docking was a simple docking of promising medicines against the crystal structure of Mpro while the altogether coming included docking against variations in conformation of the active pocket of Mpro, which generally cause to perfect outcomes. Cefuroxime, via trade name of Ceftin, was classified as the second-successful medicine from the FDA drug library via the whole method with a grid score of -49.33 [118]. Al-Khafaji and associates [124] practiced covalent docking scanning to determine potent compounds that could connect covalently, thus irreversibly, to Cys145 of the active point of Mpro. Cys145 of Mpro has been found as an important residue that can be covalently attached by compounds to impede function of Mpro [125][126][127]. They confirmed that the top 8 compounds showed a greater affinity to form covalent, irreversible bond with Cys145 of the active cavity of Mpro. Cefuroxime was the 5 th apical ranking medicine with a binding energy of -54.25 kcal/ mol while Remdesivir rated third with a binding energy of -65.19 kcal/mol [118]. Wu et. al [128] screened FDA-accepted drugs from ZINC library, and a library of recognized antiviral agents against active points all SARS-CoV-2 proteins. The binding energies of encouraging medicine candidates were articulated as ICM scores and ICM mfscores (mean force scores). The ICM score is a measure of the total experimental function of the concluded physical interaction while the ICM mfscore is an separate score of the power of drug-receptor interaction [129][130][131]. Per the ICM user guide, the score is regarded as perfect scoring to handle for docking result researches, and ICM scores less than -32 are mainly regarded to be acceptable scores [129]. Wu and co-workers analysed medicine nominees with ICM scores less than -30 or ICM mfscores less than and a mfscore of -113 [118].
Elfiky [132] also presented possible binding of Cefuroxime to RdRp. The author performed MDS with molecular docking to the binding of a few of pre-chosen medicines involving antiviral agents and Cefuroxime to RdRp. The median binding energy for Cefuroxime at -6.875kcal/mol was within the limit of error of Remdesivir at -7.16kcal/mol [118]. Dar'ya and colleagues [133] concluded that Cefuroxime may prohibit the ACE2-Spike complex.
Once, they developed a system named PolypharmDB that included the estimated binding profiles of over 10,000 confirmed and experimental medicines. PolypharmDB was then questioned for possible medicines that could prevent SARS-CoV-2 proteins of interest, which uncovered Cefuroxime as a hit 5 medicines that may impede ACE2-Spike protein complex [118]. According to the paper It is biotransformed into glycyrrhetinic acid, which has a chemical structure akin to that of corticosteroid and therefore functions as a glucocorticoid-resembling medicine, which may serve afford immune adjustment versus cytokine storm and lessen inflammation, endoribonuclease with uridine particularity, while glycyrrhizic acid was discovered to be perfect fitted for the binding spot of spike glycoprotein and further, prohibited the inlet of the virus into the host cell [140]. The binding free energy of both glyasperin A and glycyrrhizic acid was measured from the complete MD simulation trajectory through the MM-PBSA method and discovered to great binding affinity facing the specific protein receptor pocket. Hence, glyasperin A and glycyrrhizic acid could be regarded as the perfect compound from liquorice, which could get beneficial against COVID-19 [140]. Nitazoxanide is a pro-drug for tizoxanide, which has wide-spectrum antiviral characteristics, has a large numbers of viral signs and exhibits hopeful pharmacodynamics against Coronaviridae [141]. It has not yet been investigated on COVID-19 sufferers but formerly displayed a low in vitro active concentration (eC50) against Middle east respiratory syndrome coronavirus and dangerous acute respiratory syndrome coronavirus [142].
Nitazoxanide was so picked out as a perfect nominee for conceivably inhibiting SARS-Cov-2. To evaluate inhibition potential, investigators correlated the maximum serum concentration of tizoxanide (Cmax) with the in vitro eC50 for nitazoxanide for SARS-Cov-2 [143].
Previous evidences of nitazoxanide vary broadly. It is certified by the US Food and Drug Administration (FDA) for giardiasis [144]. Notwithstanding, it has been examined and utilized for many other illnesses, involving cryptosporidiosis diarrhoea in HIV patients, influenza, hepatitis viruses, rotavirus and norovirus. As such, the safety description of nitazoxanide is alternatively announced and requires clarification before likely large-scale experiment and healing in the COVID-19 pandemic.
Commonly, COVID-19 cure courses are applied for 7-14 days; so, whether nitazoxanide is safe to apply requires to be confirmed for this period [143,145]. Nitazoxanide displays an overall agreeable safety chart, with no important dissimilarity in the existence of overall AEs (adverse effects), severe or gastrointestinal AEs correlated with other antimicrobial regimens or with placebo control.
More proof is required regarding particular hepatorenal and cardiovascular effects, also the likely for teratogenicity, however existing indication provides no exact explanation for matter. Though, they advise attention and cautious screening in hepatorenal damaged patients [143]. A Mexican trial correlating nitazoxanide with hydroxychloroquine for COVID-19 is presently newcomer (US Clin-ical Trials registry number NCT04341493) participants. Additional clinic researches in COVID-19 cases should be started, but the great presented in vitro effect of nitazoxanide con SARS-COV-2 should also be proved. If competence versus SARS-Cov-2 is testified in clinical trials, nitazoxanide may depict a harmless and economical healing in the continuing pandemic [143]. As mentioned the review written by Yanfang and co-workers, aescin isolated from Aesculus hippocastanum and reserpine isolated from various Rauwolfia species [146], were both exhibit to have significant anti-SARS actions with the concentration for 50% of maximal effect (EC50) values of 3.4 and 6.0 mmol/L, accordingly [147].
Ginsenoside-Rb1, one of the pharmacologically active components of Panax ginseng [148], was presented to have activity against SARS-CoV at the concentration of 100mmol/L [147]. Boenninghausenia sessilicarpa (Rutaceae), a slender and perennial plant, has long been accepted as a coumarin-rich Chinese herbal drug dispensed in the temperate hilly regions at an altitude of 1500-2500m in southwestern China. It is traditionally utilized for the cure of fever, festers and tonsillitis. Leptodactylone, isolated from B. sessilicarpa, was discovered to possess a powerful protective action con virus-infected cells and anti-SARS-CoV action with the inhibition rate of 60% at 100mg/ ml [149]. As well as, it has been displayed that lycorine obtained from Lycoris radiata They also notify that Wi-A/Wi-N composition differentiates in various parts of Ashwagandha and guarantees attentive regard for their application [153]. Kumar  tea, since these are previously acknowledged to display antiviral activity con many RNA viruses.
They have illuminated the binding affinities and binding modes among these polyphenols containing a familiar Mpro inhibitor N3 (possessing binding affinity 7.0kcal/mol) and Mpro utilizing molecular docking investigations. Whole eight polyphenols show perfect binding affinity versus Mpro (7.1 to 9.0kcal/mol).
Pharmacokinetic examination revealed that these polyphenols own desirable drug-resemblance properties too. Altogether, their study exhibits that these three polyphenols can be exploit as promising inhibitors versus SARS CoV-2 Mpro and are encouraging medicine nominees for COVID-19 cure [161]. Some flavonoids are familiar to inhibit 3CLpro from SARS-CoV which brings about SARS. Since their sequence identity is 96%, a analogous way was performed This ligand-protein interaction research disclosed that more than half of the best twenty alkaloids and terpenoids connected desirable with the coronaviruses 3CLpro, and own binding affinities that outpaced that of lopinavir and ritonavir.