key: cord-0723570-p3oiuknd
authors: gumber, Khushbu; Pomila
title: FDA Recommended Potent Drugs against Covid-19: Insight through Molecular Docking
date: 2021-01-13
journal: Mater Today Proc
DOI: 10.1016/j.matpr.2020.12.649
sha: 9d2a242274310aa4676895c046e650dae4a67316
doc_id: 723570
cord_uid: p3oiuknd

Human Coronavirus (COVID-19) is a worldwide pandemic of 2019-20 that was emerged in China in December, 2019. More than 37,000deaths with7, 84, 440confirmed cases has been reported from around 200 different countries has been reported till now and the number is increasing every second. The spread is said to be throughhuman to human transmission via close contact or respiratory droplets produced when people cough or sneeze. No treatment for the illness has been approved yet. The urgent need is to find solution to this growing problem that has affected the whole mankind. World Health Organisation (WHO) as well as US Food and Drug Administration (FDA) arecontinuously working to find the solution. In the same line they have proposed many potent drugs that may have efficiency against the newly emerged viral infection. To supportthe efforts the present study is designed to carry out the in silicoanalysis viz. Docking studiesof around 16drugs recently recommended by US FDA by observing the interaction of test molecules with SARS proteinase.

COVID-19 is a newlyarisen human coronavirus, testified in Wuhan, China inDecember 2019 [1, 2] . The severity of the disease was earlier found only in China but now became uncontrollable problem all over the world. On January 30, 2020, it is statedasPublic Health Emergency of International Concernby WHO and later on 11 March, 2020 it was declared a pandemic.It is originated from seafood market and leading to viral pneumonia leading to the emergence of the outbreak [3] . The number of cases aregrossly increasing daily, with confirmed cases exceeding7, 84, 440 confirmed cases with > 37,000 deaths in around 200 different countries.A single stranded RNA virus ofCoronaviridae family is considered to be thecause of this severe acute respiratory syndrome [4] [5] [6] [7] . The terrible manifestations of this infection include fever, cough,and breath failure allied with respiratoryproblem. High pervasiveness of hospitalization and with mortalityrisk of more than 15%, and lack of prophylacticvaccines and therapeutic conventions, embrace serioustasks of SARS at time of worldwide outbreaks [8] [9] [10] [11] . TheSARS genome encodes 2 polyproteins thatare cleaved to dissimilar functionalproteins of envelop, spike,nucleoprotein,polymerase, replicase, and membrane [12] [13] [14] . WHO is putting huge efforts in finding specific treatments with many under clinical trialsbefore reaching the final solution.In scientific world, the race is on to find a drug that might help save severely ill patients.But obviously even with rapid government approval, it could take months to develop new drugs from scratch that might be effective against the virus.Thus computer modelling studies on certain drugs already approved by the U.S. Food and Drug Administration, to assess their potential in combating the coronavirus is something that can be done at present.Several antiviral drugs such as Darunavir, Nelfinavir, and Saquinavir; the ACE inhibitor Moexipril; the chemotherapy drugs Daunorubicin and Mitoxantrone; cholesterol-lowering statin rosuvastatin;the painkiller Metamizole; the antihistamine Bepotastine; and the antimalarial drug Atovaquone, Chlorquinone and hydroxychloroquine are some of the drugs under scrutiny [15] . The present study is aimed to further support the potency of these test molecules on the basis of their interaction withSARS proteinase through docking experimentto comprehend the mechanismsused forschemingmorepromising drugs against SARSinfection.

Docking strategy was utilized to find the binding efficiency of test molecules in active site of SARS-CoV main protease, using AutoDockTools-1.5.6 software. Enzyme comprises the crystal structureof Mpro(PDBID: 1UK3) [16] . It is acquired by the X-Raydiffraction technique and developed at the resolutions of 2.4 Å [17]. The enzymes were made to bind with compound and docking score was calculated. The more negative energy represents the effective binding and hence activity of compound.

Sixteen different FDA recommended drugs were considered for the study: antiviral drugs such as Darunavir (I), Nelfinavir (II), and Saquinavir (III); HIV drugs Ritonavir (IV), and Lopinavir (V); the ACE inhibitor Moexipril (VI); the chemotherapy drugs Daunorubicin (VII); cholesterol-lowering statin rosuvastatin (VIII); the painkiller Metamizole (IX); and the antimalarial drug Atovaquone (X), Chlorquinone(XI) and hydroxychloroquine (XII); blood pressure drug Losartan (XIII); antibiotic Metformin (XIV); Schizophrenia drug haloperidol (XV); against Ebola Remdesivir (XVI). The compounds were preparedwith help of PubChem database and the 3D structure of the ligands wereregainedin SDF format from PubChem Compound database followed by conversion in the PDB format and optimization using Marvin Sketch. Molecular mechanics were utilized to createtherepresentative geometry for the majority of test moietiesdue to the fact of being extremely parameterized. The pdb-files were converted to PDBQT by using AutoDockTools-1.5.6 [18, 19] .

The active binding site was found from the selected protein by CASTp2.0 server [20] .

The protein was saved as pdb-file and the attached water molecules were deleted and polar hydrogens were added in AutoDockTools-1.5.6and then saved as PDBQT. Before dstarting the next procedure, docking grid box was set with centrex=82.665, centrey=-15.887, centrez=31.008 of sizex=70, sizey=40, sizez=56.AutodockVina was used to carry out docking and PyMol for virtual screening.

Allouput files corresponding to 16 ligands were obtained from AutoDockVina were analysed by using PyMol. The interactions between docked molecule and protein can be seen via hydrogen bonding with different amino acid residues of protein and the given compound.Theindication of hydrogen bonds were signifiedby dashed lines between the atoms,while hydrophobic bonding are indicated by an arc with spokes radiating towards the atoms of ligands.

The selected molecules were investigated for their best co-inhibiting activities in the enzyme. Therefore, molecular docking of designed hybrids were carried out into the active site of the enymeSARS-CoV main protease(PDBID: 1UK3) using AutoDockTools-1.5.6. All the test molecules fitted into the binding pocket of SARS-CoV main proteaseand showed appreciable docking score. Out of 16test drugs, 14 drugs showed docking scores ≥-7.0 Kcal/mol. Best among them with docking score of more than -10.0 Kcal/mol that shows strong binding in the pocket of an enzyme are Saquinavir (-11.5 Kcal/mol) followed by Nelfinavir (-11.1 kcal/mol); Daunorubicin (-10.7 kcal/mol) and Darunavir (-10.2 Kcal/mol). The results with structural analysis are shown in Table 1 Binding modes of the selected compoundswere studied using Pymol. Hydrophobic interaction as well as hydrogen bonding results in the strong binding interactions. The prominent bonding in Saquinavir, Nelfinavir and Daunorubicindue to hydrogen bond interactions in the binding pockets of the target enzyme is shown in figure 1-3 and for sake of comparison absence of bonding interactions leading to poor binding energy of metformin is shown in Figure 4 . Saquinavir form three hydrogen bond with three amino acid residuesi.e. Glutamic acid (286), aspartic acid(286)and third with serine (281). Nelfinavir also showed three hydrogen bond with active arginine (6), glutamic acid (286) and aspartic acid.On the other hand, Daunorubicinform only hydrogen bonding with arginine (6) and Glutamic acid (286). On the other hand,Metformin showed no interaction with lowest docking score among all. Three among these four strongest binding showing molecules belongs to the category of anti-viral whereas the Daunorubicin is a chemotherapy drug. Structural analysis of these molecules indicated that all these have multiple oxo-groups in form of amide linkage in all the three anti-viral molecules whereas in Daunorubicin having a special quinone moiety [21] . The amide linkage in Ritonavir and Lopinavir also make the two HIV agents another promising molecules followed by quinone ring containing Atovaquinone. 

The antiviral drugs (Saquinavir, Nelfinavir and Darunavir) showed the strongest binding efficiency along with chemotherapy drug (Daunorubicin). The HIV drugs also showed good binding efficiency making them a good option after these antiviral molecules. These molecules can be employed until a new molecule with targeted action is not obtained. But the clinical trials are must before recommending a drug for combating the disease and the efforts for developing new drugs with more promising activity must be kept on in the same line. 

Pneumonia of unknown etiology in Wuhan, China: Potential for internationalspread via commercial air travel

The continuing2019-nCoV epidemic threat of novel coronaviruses to global health-the latest2019 novel coronavirus outbreak in Wuhan, China

Antiviral drugs specific for coronavirusesin preclinical development

Characterization of a novel coronavirus associated with severeacute respiratory syndrome

Severe acute respiratorysyndrome (SARS)-paradigm of an emerging viral infection

Hindsight: a re-analysisof the severe acute respiratory syndrome outbreak in Beijing

Current status of anti-SARS agents

Viralshedding patterns of coronavirus in patients with probable severeacute respiratory syndrome

Identificationnd containment of an outbreak of SARS in a community hospital

Exploring the binding mechanism of the mainproteinase in SARS-associated coronavirus and its implication toanti-SARS drug design

Molecular mechanisms of severeacute respiratory syndrome (SARS)

Correlation betweendissociation and catalysis of SARS-CoV main protease

Discovery, synthesis, and structure-based optimization of a seriesof N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188)as potent noncovalent small molecule inhibitors of the severe acuterespiratory syndrome coronavirus (SARS-CoV) 3CL protease

Lopinavir; A Potent Drug against Coronavirus Infection: Insight fromMolecular Docking Study

A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians

AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading

Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design

Antiviral activities of peptide based covalent inhibitors of the Enterovirus 71 3C protease