Coronavirus Disease 2019 (COVID-19). Structural and Pharmacophore mapping of RNA dependent RNA polymerase (RdRp)

In-silico study


Research Paper (undergraduate), 2021

37 Pages, Grade: A+


Free online reading

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is a highly contagious disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can be transmitted from person to person. Currently, no vaccine and antiviral treatment available to control this deadly virus but preventive measures and a few re-purposed drugs are available to combat COVID-19. RNA dependent RNA polymerase (RdRp) also named as nsp12 has key role in the replication or transcription of the viral machinery. Anti-viral drug such as Remdesivir (approved drug) has been shown the inhibiting activity against SARS-COV-2 RdRp. The present study will be design to execute a rational screening of natural compounds against SARS COV-2 to cure COVID-19. For this purpose, firstly protein and structure conservation analysis of SARS COV-2 RdRp was performed to check the mutations. Secondly, a library of 15,000 phytochemicals were developed from literature search, PubChem, zinc database and MPD3 database. This library was employed for molecular docking and simulation studies against SARS-COV-2 RdRp. The top-ranked natural compounds were subsequently be subjected to In-silico pharmacokinetic and pharmacological study. Top seven natural compounds (Monotropein, Docetaxel, Daphnodorin M, Spinasaponin A, Neohesperidoee, Paucin, Saikosaponin B2) were selected based on their interaction with binding pocket residues (618,619,759-761,811-814)), Energy function score (-16.38, -17.83, -16.15, - 17.65, -15.80, -20.03, -18.11) and their ADMET properties. Our study revealed that Remdesivir has potential to bind with only active site residues that present in conserved motifs A and C of palm domain in SARS-COV-2 RdRp, but our purposed seven best compounds also showed binding affinity with another catalytic active site motif E(residues 811-814). Although this computational work is not experimentally determined but the structural information and selected compounds might help to design an anti-viral drug to combat SAR-COV-2 by inhibiting the activity of SARS-COV-2 RdRp.

Keywords: SARS-CoV-2, COVID-19, molecular docking, natural medicinal compounds, Nsp12- RdRp

1.0 Introduction

Coronaviruses (CoVs) are the largest group of viruses belonging to the Nidovirales order, which includes Arteriviridae, Coronaviridae, Roniviridae, and Mesoniviridae families. Coronaviruses have helically-symmetrical nucleocapsids most commonly found among negative-sense RNA viruses [1-6]. These viruses comprise one of two sub-families, one is Coronaviridae family and another being is the Torovirinae family. The Coronaviridae is further sub-divided into 04 genera, such as; alpha, beta, gamma, and delta coronaviruses. Viruses having coronavirdae family were initially sorted into these genera based on analysis of serology. Coronaviruses have crown-like spike structure on the surface with a large enveloped RNA genome. Human coronaviruses were first time identified in an upper respiratory tract in the 1960s. Recently seventh human coronavirus are known to belong to these genera (a, ß, y , and ô) 7.

Novel severe acute respiratory syndrome coronaviruses (SARS-CoV-2) includes five other new human coronaviruses were identified as a human pathogen (human to human transmission) 8. SARS-CoV-2 belongs to the beta viruses class having a coronaviridae family [9, 10]. Recent studies on phylogenetic analysis of SARS-CoV-2 genomes categorized the SARS-COV-2 into three types as A, B and C types based on phylogenetic clustering. Type A is the ancestral type that includes the bat as out-group. Type A and type C both these types found in most parts outside the East-Asia and most abundantly found in European and American populations. Type B is found most commonly in East Asia but its ancestral genome appears not in East Asia without a process of mutation. [32, 49, 50]. SARS-COV-2 causes infectious severe disease such as severe acute respiratory syndrome (COVID-19) 11. In the past two decades, the mortality rates are 10% for SARS-CoV and 37% for MERS-CoV 12.

World Health Organization (WHO) declared a Public Health Emergency of International Concern (PHEIC) for the pandemic threats of SARS-COV-2 outbreak, on January 2020 [13-16]. The first case of SARS-Cov-2 was reported on December 30, 2019, in China city (Wuhan, on January 10, 2020). And the first whole-genome sequence of SARS-COV-2 was released on the 21st of January by using reverse-transcription polymerase reaction (RT-PCR) [1, 17, 18]. Clinically, the potent anti-coronaviruses therapies can be distinguished in two categories, first category target the human immune cell and the second category directly affects SARS-COV-2 19. There are no approved drugs or vaccine available to date and the focuses is on addressing the symptoms that may include pneumonia, dry cough, and fever 20.

SARS-COV-2 is a single-stranded positive-sense RNA-virus that possesses a large viral RNA genome (+ssRNA) with started 5-cap to 3-poly-A tail. The genome size of SARS-COV-2 is approximately 30kb which is the largest among all RNA viruses groups [21-23]. Recent studies showed that SARS-CoV-2 have a similar genomic resemblance with other beta-coronaviruses group and this virus divert from SARS-CoV, MERS-CoV, consisting of the 5-untranslated region (UTR), and replicate complex of ORF with encoded non-structural protein, an envelope protein (E), spike protein (S), non-structural open reading frames and membrane-nucleocapsid proteins (N) 1. Typically, the genome of SARS-COV-2 consists of 06 open reading frames (ORFs) [8, 24]. The non-structural proteins have a vital role in SARS-COV-2 replication [25, 26].

The RdRp (RNA-dependent RNA polymerase) also known Nsp12 is the vital, central part of coronaviruses in replication/transcription, catalyzes the synthesis of viral-RNA, and the domain of polymerase as conserved building of the family of viral-polymerase [27-29]. The RdRp is an important participant for encoded protein in viral-RNA-genomes [30, 31]. The RNA-directed- RNA polymerase (RdRp) in SARS-CoV-2 play important role for replication and transcription of the viral RNA genome as SARS-CoV-2 has approximately 80 to 89.10 % nucleotides identity with original SARS-CoV genome viruses. [22, 32-34].

Phytochemicals are extracted from medicinal plants 35, which are of two categories; primary phytochemicals are consisting of amino acids, chlorophyll, proteins, and starch-sugars, and secondary constituents are terpenoids, flavonoids, steroids, alkaloids, pectin-like compounds 36. Phytochemicals are used for the biological-reaction of antifungal, anti-inflammatory, anti-viral activities 37. A wide variety of active phytochemicals including alkaloids, organosulfur compounds, limonoids, sulfides, polyphenolics, chlorophyllin, phenols, furyl compounds, proteins and peptides, thiophenes, polyenes, saponins, lignan, glycosides, disaccharides (oligo­saccharides), flavonoids, anolides, antimetabolites, multiple-steroids compounds, riboflavin and many other have been found to have acted as therapeutic in nature against different genetically and functional diversity of viruses [38-44]. In silico -based activity analyses revealed, especially the phytochemicals (medicinal plants) have attractive bioactive compounds that have significances against various pandemic diseases like SARS-CoV2, COVID-19 that could be used to develop antiviral drugs with low side-effect potency[45-48].

In Bioinformatics, computer-aided drug design (CADD) has key role in streamline-drug discovery, development process, drug-design, biological and chemical information about ligands and interaction 51. CADD also used for the designing of in-silico filters to eliminate compounds with undesirable properties and it also used to identify the drug targets in minimum time limits [52-54]. On account of critical analysis of SARS-CoV-2-RdRp the in-silico approach was used. For this purpose, the library of 15,000 phytochemicals were screened via docking analysis with SARS- CoV-2 RdRp. We successfully identified Seven top-ranked compounds including Monotropein, Docetaxel, Daphnodorin M, Spinasaponin A, Neohesperidoee, Paucin, Saikosaponin B2, while we used Remedesvir as a target. The potent compounds were also evaluated for Toxicity­assessment and drug-likeness which suggests opportunities for the further refinement of the phytochemicals lead to compounds against COVID-19 through experimental study. Hence, the present study was carried out to obtain structural analysis against the SARS-CoV-2 RdRp (nsp12) and to discover potential natural anti-SARS-CoV-2 drugs.

2.0 Methodology

Structure-based virtual screening of phytochemicals using molecular docking

2.1 Data Collection of Nsp-12-RdRp

The sequence of SARS-CoV-2-RdRp (accession no: YP_009725307.1)27 was downloaded in FASTA Format from National Center for Biotechnology Information (NCBI). The protein structure of SARS-CoV-2 RdRp was selected from Protein Data Bank (PDB) using id : 6M71.

2.2 RdRp sequence and conservation analysis

The binding pocket's key residues of RdRp were predicted through meta-COACH-server 55. The predicted key residues confirmed through literature and multiple sequence alignment of COVID-19-RdRp with Human-SARS-CoV, MERS-CoV, Bat-CoV using Clustal-W were performed56 and the alignment figure was created through ESPript3 57. The physiochemical properties of SARS-CoV-2-RdRp such as the composition of atomic and amino acid composition, grand average of hydropathicity (GRAVY), instability-index & isoelectric point were determined using of ProtParam tool of ExPASy 58.

2.2 Structural analysis of SARS-CoV-2-Nsp12

The solved structure of Nsp12-RdRp (SARS-CoV-2) were retrieved from PDB by using PDB id: 6M71 with a resolution value of 2.9Ä. Therefore, the predicted SARS-CoV-2-RdRp structure is the complex with two cofactor proteins Nsp7, Nsp8. Next, mutational analysis was performed by the superimposition of SARS-CoV-2 RdRp and SARS-CoV (id: 6NUR), and this analysis was done through chimera 59.

2.3 Structure refinement and energy minimization SARS-CoV-2 Nsp12 for molecular docking

Solved structure of the SARS-CoV-2 nsp12 was minimized through chimera by selecting steepest descent steps (1000), conjugate gradient steps(1000) and adding the gasteiger and hydrogen charges to remove clashes and unnecessary atoms from protein structure[60, 61].

2.4 Phytochemical library and ligands preparation

2D conformation of different 15,000 medicinal compounds were collected from different databases such as maps, PubChem 62, zinc databases 63, MPD3-databases 64, and Drug bank 65 in SDF file format and prepared the ligand by adding hydrogen charges, through protonate 3D while energy minimization was done via selecting MMFF94x force-field 66 in Molecular operating environment (MOE) and edit these ligand to the MOE databases for the molecular docking.

2.5 Molecular docking

The virtual screening of the compounds was applied to the library of 15,000 phytochemicals that have antiviral effects. These medicinal compounds were collected from previous studies. The virtual screening was applied using the molecular docking approach through MOE 67, and PyRx tool 42, The targeting molecular docking approach was used to screen the potential anti­viral top-compounds against SARS-CoV-2 nsp12.

2.6 ADMETsar Property

The molecular-based physiochemical properties and drug likeliness properties of best docking score phytochemicals were analyzed using the tool Molinspiration server 68, that gives a prediction based results ‘rule of five' (Ro5) on the basis of molecular properties such as; MloP value less than 05%, H-bond-acceptors fewer as less than 10, less than 05 H-bond-donors, and molecular weightless and equal 500 Daltons 69. Further, the quantitative analysis including deposition, metabolism, excretion, absorption, various toxicity screening models such as oral acute toxicity, organ toxicity, cytotoxicity, mutagenicity, hepatotoxicity, genetic toxicity of ADMET profiling of top selected compounds was in-silico based observed through ADMETsar-server, and ProTox-II webserver [70, 71].

3.0 Results and Discussion

3.1 SARS-CoV-2 RdRp Sequence and Conservation analysis:

The results of the multiple sequence alignment showed that RdRp was conserved among all SARS-COV-2 genomes. Furthermore, Multiple sequence alignment revealed that binding motifs in SARS-2 (A, C and E) were also conserved among Human-COV, SARS-COV, MERS-COV and Bat-COV. SARS-COV-2 RdRp sequence was aligned with its close homologous sequences (Human-COV, SARS-COV, MERS-COV Bat-COV) and alignment results with 70% sequence consensus shown in figure(A). Sequence comparison of RdRp with its closest homologous sequences showed high sequence identity and query coverage such as 96.65, sequence identity and 100% query coverage with bat-COV. RdRp further showed sequence identities as 96.35%, 96.35%, and 71.31% with human SARS coronaviruses, SARS-like coronaviruses and MERS coronaviruses respectively and query coverage was 100% of all RdRp protein sequences. Above analysis was accordant with the previous studies [72-74] that revealed a high sequence similarity between SARS-COV-2 and SARS-like coronaviruses than MERS and both shared a common ancestor with bat-COV.

The Physiochemical properties of RdRp were predicted through ProtParam 75. The analysis revealed the physiochemical properties such as RdRp protein length was 932 amino acids having 106660.24 Da molecular weight. The GRAVY score and instability index were computed as 0.224 and 28.32 that classifies the protein as stable protein depicting that hydrophilic residues are able to establish hydrogen bonds (Table 1).

3.2 SARS-CoV-2 RdRp Structure analysis:

Solved structure of SARS C0V-2-RdRp was selected from the Protein Data Bank (PDB ID:6M71) that contains 932 amino acid residues 76. Structures of nsp7 and nsp8 present in RdRp as cofactors also comprising a similar structure as in SARS-COV 77. The N-terminal domain of the RdRp (60-249 residues) resembled the structures of RdRp of all nidoviruses nucleotidyltransferase domain (NiRAN) 78. Polymerase domain with cupped right-hand shape located at the 367-920 residues and studies revealed that all the polymerase domains have the cupped right-hand shape architecture 79. Both the NiRAN and polymerase domains are interconnected through an interfacial domain comprising the residues (250-365) 76. The starting 116 residues of N-terminus and some residues of NiRAN domain (4-28 and 51-249) were not fixed in SARS-COV but resolved in SARS-COV-2 77. Disulfide bonds also observed in RdRp of SARS-COV-2 between 301-306 and 487-645 residues.

The structure of the SARS-COV-2 polymerase domain and other viral polymerase domains maintain a conserved structure 80 and comprising of three subdomains such as a Fingers, a palm, and a thumb subdomains. These subdomains having the residues as a finger=366-581 and 621- 679a.a, palm=582-620 and 680-815a.a and thumb=816-920a.a respectively. There are seven conserved motifs in SARS-COV-2 RdRp polymerase domain and these motifs(A-G) are present in Palm subdomain formed an active site chamber 81. Furthermore, motifs A includes the residues as 611-626 motif C having residues as 753-767 and D618 and SDD759-761 are conserved among all polymerase family viruses 82. Other Conserved Motifs also present in SARS-COV-2 RdRp such as B (682,681,691 residues), D (783 and 786), E (812,813,814 residues), F (545,551,553 and 555 residues) and G (499 and 504 residues). Structure of SARS-COV (PDB id:6NUR) and SARS-COV-2 (PDB id:6M71) both these structures were superimposed giving 0.52(Angstrom), rmsd value that depicts the conservation of RdRp structure. A few mutations were observed in SARS-COV-2 in comparison with SAR-COV as shown in figure(C).

Remdesivir is used to inhibit SARS-COV-2 virus replication [1, 83]. The conformation of active site residues elucidated via literature, couch server and analyzing the interaction of remdesivir with binding pocket key residues (618,619,759-761,811-814) but Remdesivir shown interaction with A and C motifs residues of SARS-COV-2 RdRp not with residues of motif E(811-814). Overall RdRp structure and Remdesivir interaction shown in figure(B).

3.3 Molecular Docking

A comprehensive library of 15,000 natural compounds from herbal and traditional Chinese medicinal plants was docked against SARS-CoV-2 RdRp and top seven poses of phytochemicals with RdRp binding pocket residues. Selection criteria was based on stringent filter includes maximum occupancy of binding pocket residues (motif A, C and E) with maximum binding affinity, least RMSD, minimum energy function score and least gibs free energy. Noticeably these selected compounds showed minimum binding energy between -17.83kcal/mol and - 20.83kcal/mol.

Out of 15,000 phytochemicals, the seven best poses such as Monotropein (PRO620, TYR619, ASP760, ASP761, SER814, PHE812, ASP618, CYS813, GLU811), Docetaxel (TYR619, SER759, ASP760, ASP761, ASP618, GLU811, PHE812, SER814, CYC813), Daphnodorin M (TYR619, ASP618, SER659, ASP760, ASP761, CYS813, SER814, PHE812, GLU811), Spinasaponin A (ASP760, PRO620, TYR619, ASP618, GLU811), Neohesperidose (ASP760, ASP761, ASP618, SER814, GLU811), Paucin (SER759, ASP760, ASP761, TYR619, ASP618, CYS 813, PHE812, GLU811), Saikosaponin B2 (ASP760, ASP761, TYR619, ASP618, CYS813, PHE812, GLU811), were selected based on minimum scoring function (-16.38, -17.83, -16.15, -17.65, -15.80, -20.03, -18.11), lower RMSD (0.92, 1.89, 1.96, 0.85, 0.99, 1.59, 1.86) and maximum occupancy with target active site residues of SARS- CoV-2-RdRp that present in conserved motifs such as A (conserved residues 618,619), C (conserved residues759,760,761) and E ( conserved residues 811-814) motifs shown in (Table 2).

3.4 ADMETsar properties

ADMET drug likeness analysis of selected phytochemicals was performed through molinspiration 84based on Lipinski rule of five (Ro5). The purposed phytochemicals displayed 0,1,2 violations to Lipinski's Ro5 and exhibited acceptable drug-like properties like HBA (6,11,11,5,6,10,10), HBD (4,0,6,1,4,0,0), MloP values (5.90,-3.43,0.51,1.62,5.90,-4.48,0.80) shown in Table

3. Furthermore, pharmacokinetic properties were predicted through ADMETsar server for the validation of phytochemicals' drug likeness shown in Table 4.

Next, toxicity assessment of top ranked potential compounds obtained after the docking analysis with different toxicity-modules. Among these compounds such as Monotropein obtained the genetic toxicity (LD50 = 1000mg/Kg) as class 4, prediction accuracy 68.07% shown in (fig D1). Docetaxel obtained the genetic toxicity (LD50=13mg/Kg), as class 2, accuracy prediction 72.9% shown in (fig D2), Daphnodorin M obtained the genetic toxicity (LD50=517mg/Kg), as class 4, prediction accuracy 69.26% shown in (fig D3), Spinasaponin A obtained the genetic toxicity (LD50 = 100 mg/Kg) as class 3, prediction accuracy 70% shown in (fig D4), Saikosaponin B2 obtained the genetic toxicity (LD50=1000mg/Kg) as class 4, prediction accuracy percentage 68.07% shown in (fig D5), Neohesperidose obtained the genetic toxicity (LD50 = 2000 mg/Kg) as class 4, prediction accuracy 100% shown in (fig D6), and Paucin obtained the genetic toxicity (LD50=4000mg/Kg) as class 4, prediction accuracy 100% shown in (fig D7), also shown in Table 5.

For the prediction of organ toxicity with special reference observed as hepatotoxic inactive in nature of selected compounds with probability score (0.72,085,0.77,0.97, 0.72,0.79,0.90) respectively. The prediction of genotoxicity with special to cytotoxicity and mutagenicity revealed that among seven compounds was observed inactive, and cytotoxicity with the probability score of 0.84, 0.73,0.770.51,0.84,0.70, and 0.88, and also observed in mutagenicity revealed with the probability score of 0.63,0.50,0.63,0.63,0.87,0.66, and 0.73 among seven compounds including Monotropein, Docetaxel, Daphundorin M, Spinasaponin A, Neohesperidose, Paucin, , Saikosaponin B2, and as a target Remedesvir respectively shown in Table 6.

Our analysis revealed that remdesivir showed the binding affinity with the motif A residues (618,619) and motif C residues (760,761) but the seven best selected compounds showed binding affinity with another catalytic binding pocket motif E residues (811-814). Herein, we found another catalytic binding site that help in viral replication that is motf E. From the literature review of the top seven selected phytochemicals, we noticed that the role of Monotropein in other domain acts as neuroprotection, antitumor, anti-inflammatory, cancer cell lines abnormalities, antiviral agent, and regulation of pathological in oxidation products [85-87] , Docetaxel, Daphnodorin M, Paucin role as in antiviral activity 88 in cancer, signal transduction and antiviral agent [89, 90] 91, anti-diabetes drugs in morphine biological activities, RORa Regulates the Expression and the Transcriptional 92, interaction development-interaction functions, [93-95] , the role of Spinasaponin A has been used to inhibit tumor cell growth by cell cycle arrest and apoptosis and cognitive function [96, 97]. The Saikosaponin B2 inhibited viral attachment, strongly inhibited HCV infection at non-cytotoxic concentrations, on human coronavirus 229E and diabetic disorders [98-100]. Other functions of Neohesperidose as antiviral, anti-diabetic, 101, antioxidant agents in cancer treatment, antimicrobial-pharmacological, and immunomodulatory activities [102-104].

4.0 Conclusion

In our study, we found that SARS-COV-2 RdRp is conserved among all genomes of SARS-COV- 2.Our study also revealed that RdRp has high sequence identity with bat SARS-like coronaviruses (96.65%) that depict the high homology between SARS-COV-2 and BAT-like-COV. Our study revealed active site key residues are present at the conserved motifs A, C and E. FDA approved drug (Remdesivir) also tested in our screening of the compounds and it is found that this drug also has a good binding affinity with active site residues (618,619,760,761). Our analysis showed that seven best selected phytochemicals also have binding affinities with the conserved motif E. Herein we anticipate that the seven best poses that are discussed in this study might have more inhibition effects than remdesivir to combat COVID-19. Phytochemicals already are being used to cure many viral diseases. We also screened the phytochemicals library of 15000 compounds that has anti­viral effects and we selected the top seven compounds such as (Monotropein, Docetaxel, Daphnodorin M, Spinasaponin A, Neohesperidose, Paucin, Saikosaponin B2, and as a target Remedesvir) that could be helpful in inhibiting RdRp activity hence Virus replication. The selection of the top seven compounds based on their minimum energy function score, maximum occupancy with binding pocket residues and least RMSD. Our analysis also showed that seven best selected phytochemicals also have binding affinities with the conserved motif E. Herein we anticipate that the seven best poses that are discussed in this study might have more inhibition effects than remdesivir to combat COVID-19 and in-vivo and in-vitro analysis has to be required to use these potential compounds against SARS-COV-2 disease.

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Table1: Physicochemical parameters of SARS-CoV-2-RdRp through protparam

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Table2: Interactive top phytochemical compounds (phytochemical name, class, plant name)

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Table 3: Lipinski rule of five of bioactive compounds

Table 4: ADMET Profile of top ranked compounds, Enlisting Absorption, Metabolism and Toxicity related drug like parameters of candidate compounds

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Table 5: Prediction of oral acute toxicity, class and accuracy, organ toxicity and genetic toxicity endpoints of candidate compounds

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Table 6: Prediction of genetic toxicity endpoints of candidate compounds

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Figures: dose value distribution graphical representations

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Distribution of dose value

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Figures of top ranked poses in molecular docking:

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Figure D 1: Docked Monotropein in complex with RdRp-Nsp12 with maximum occupancy of binding pocket key residues e.g, PRO620, TYR619, ASP760, ASP761, SER814, PHE812, ASP618, CYS813, GLU811 and binding residues shown in red colour. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown.

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Figure D 2: Docked Docetaxel in complex with RdRp-Nsp12 with maximum occupancy of binding pocket key residues e.g, PRO620, TYR619, ASP760, ASP761, SER814, PHE812, ASP618, CYS813, GLU811 and binding residues shown in red colour. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown.

Figure D 3: Docked Daphnodorin in complex with RdRp-Nsp12 with maximum occupancy of binding pocket key residues e.g, PRO620, TYR619, ASP760, ASP761, SER814, PHE812, ASP618, CYS813, GLU811 and binding residues shown in red colour. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown

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Docked Spinasaponin A in complex with RdRp-Nsp12; with maximum occupancy binding pocket residues e.g, ASP760, PRO620, TYR619, ASP618, GLU811residues shown in red colour. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown.

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Figure D 5: Docked Saikosaponin B2 in complex with RdRp-Nsp12; with maximum occupancy of binding pocket residues e.g. ASP760, ASP761, TYR619, ASP618, CYS813, PHE812, GLU811. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown in red colour.

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Figure D 6: Docked Neohesperidose in complex with RdRp-Nsp12; with maximum occupancy of binding pocket residues e.g., of ASP760, ASP761, ASP618, SER814, GLU811. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown in red colour.

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Figure D 7: Docked Paucin in complex with RdRp-Nsp12; with maximum occupancy of binding pocket residues e.g. SER759, ASP760, ASP761, TYR619, ASP618, CYS 813, PHE812, GLU811. The docked pose of compound highlighting the most active residues of protein's binding pocket is shown in red colour.

Figure A: Multiple Sequence Alignment of RdRp with close homologs having 70% sequence consensus.

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Figure B: Structure of nsp12 that contains Finger domain (forest green), Palm domain(cyan), Thumb domain (orange red) and NiRAN domain(yellow). The grey and dark blue colors represented nsp8 and nsp7 respectively as cofactors in nsp12. Binding pocket residues represented in red color. Remdesivir interact with binding pocket shown in dotted circular outline with nsp12 binding pocket residues. Different motifs represented at left upper corners with domains edges in different colors like A (corn flower blue), B(dark grey), C(purple), D(red), E(blue), F(brown), G(olive green).

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Table Figure C: SARS-COV-nsp12 superimposed with the SARS-COV nsp12 structure. SARS- COV-2 nsp12 colored magenta and SARS-COV nsp12 labeled as sky blue color and all identified mutations are highlighted in yellow color in structure but written in black color.

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[...]

37 of 37 pages

Details

Title
Coronavirus Disease 2019 (COVID-19). Structural and Pharmacophore mapping of RNA dependent RNA polymerase (RdRp)
Subtitle
In-silico study
College
Governament College University Faisalabad  (Department of Bioinformatics and Biotechnology)
Course
Bioinformatics
Grade
A+
Author
Year
2021
Pages
37
Catalog Number
V1160728
ISBN (Book)
9783346566829
Language
English
Keywords
coronavirus, disease, covid-19, structural, pharmacophore, rdrp, in-silico
Quote paper
Muhammad Mazhar Fareed (Author), 2021, Coronavirus Disease 2019 (COVID-19). Structural and Pharmacophore mapping of RNA dependent RNA polymerase (RdRp), Munich, GRIN Verlag, https://www.grin.com/document/1160728

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