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Bioinformatics Analysis of SARS Proteins and Molecular Dynamics Simulated Structure of an Alpha-helix Motif

Authors:
  • Samsung SDI, South Korea, Suwon

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The complete sequencing of the severe acute respiratory syndrome (SARS) coronavirus (CoV) within a short span of time is a remarkable achievement, which has given the scope for extensive research on the virus. 1 Sequence analysis reveals the phylogeny of SARS-CoV that the genome has most of the characteristic features of a coronavirus, but it belongs to a new group which is sufficiently different from all known coronaviruses. All the coronaviruses consist of four important structural proteins: spike glycoprotein (S), small envelope protein (E), matrix glycoprotein (M) and nucleocapsid protein (N). The E protein comprised of at least 76 amino acids (aa) is a pivotal player in the morphogenesis of the virion envelope by interacting with the M protein.
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... The coronavirus-2 or SARS-CoV-2 genome translates four structural proteins, namely small envelope protein (E), spike glycoprotein (S), matrix glycoprotein (M) and nucleocapsid protein (N). 34 Next to the four structural genes, there are two proteases, namely the papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro). The latter is required for coronavirus maturation, which plays a prime role for the viral life cycle and makes it an interesting target for anti-COVID drug development. ...
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Background: Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro). Material and Methods: Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals. Results and Discussion: From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained. Conclusion: In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.
... The coronavirus-2 or SARS-CoV-2 genome translates four structural proteins, namely small envelope protein (E), spike glycoprotein (S), matrix glycoprotein (M) and nucleocapsid protein (N). 34 Next to the four structural genes, there are two proteases, namely the papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro). The latter is required for coronavirus maturation, which plays a prime role for the viral life cycle and makes it an interesting target for anti-COVID drug development. ...
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Full-text available
Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the strategies employed by a handful of researchers is the so-called drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease in the framework of molecular docking. This work also discusses the profile of druggability of the best binding candidates as well as their inherent reactivity using ADMET and quantum mechanics methods respectively. From the calculations performed, four candidates show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. Molecular electrostatic potential, Fukui functions and frontier molecular orbitals are scrutinized to discuss the global and local reactivity of these candidates. Further in-vitro and in-vivo investigations are needed to shed light on the possible mechanism of pharmacological action of the proposed ligands.
... The coronavirus-2 or SARS-CoV-2 genome translates four structural proteins namely small envelope protein (E), spike glycoprotein (S), matrix glycoprotein (M) and nucleocapsid protein (N) (Reddy et al., 2003). Over and above the four structural genes, two proteases: (i) papain-like protease (PLP) and (ii) 3-chymotrypsin-like protease (3CLpro) or the main (M pro ) protease required for the maturation of coronaviruses, which co-translationally cleaves the two polypeptides into mature non-structural proteins (NSPs) (Lim et al., 2000) that is crucial for the viral life cycle, making it an eye-catching target of anti-COVID drug development (Lu et al., 2006;Xia & Kang, 2011). ...
Article
SARS-CoV-2 Mpro is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 Mpro. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 Mpro, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 Mpro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 Mpro by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (ΔGBind = −28.31 kcal/mol) due to an increased favorable van der Waals (ΔEvdw) interactions and decreased solvation (ΔGsolv) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (−6.85 kcal/mol), KNI-227 (−18.36 kcal/mol), KNI-272 (−15.69 kcal/mol) and KNI-1931 (−21.59 kcal/mol) against SARS-CoV-2 Mpro. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 Mpro drugs. Communicated by Ramaswamy H. Sarma
... A genome group of four encodes for a coronavirus is 5′-leader-UTR-replicas (ORF1ab) -spike glycoprotein (S), little envelope protein (E)-membrane, matrix glycoprotein (M), nucleocapsid protein (N), 3′UTR-poly (A) tail. [8] 3CL-pro main protease presented in four matured structural genes is vital for coronavirus life cycle by making it a target of anti-corona viral drug by sequence alignment 3CLpro-2. The crystal structure of COVID-19 (PDB ID: 6LU7) [9] contains 9 alphahelices and 13 beta-strands that make up three distinct domains. ...
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An exclusive approach towards the synthesis of novel 3-(hydroxymethyl)-2-phenyl-2,3 dihydroquinolin-4(1H)-one and it's in-silico evaluation as inhibitor of COVID-19 main protease. The one-pot synthesis of an established procedure Claisen ester condensation reaction was sodium hydride mediated with intramolecular cyclization with solvent free conditions. The structures of the synthesized compound were confirmed by IR, 1H,13C NMR, and EI-MS spectral studies. Chemo-informatics study showed that the compound obeyed the Lipinski's rule, PASS, Swiss ADME. Computational docking analysis was performed using PyRx, AutoDock Vina option based on scoring functions. In-silico molecular docking study results demonstrated Greater binding energy and affinity to the active pocket the N3 binding site of the Coronavirus primary protease.
... A number of pharmaceuticals already being tested [3][4][5], but a better understanding of the underlying pathobiology is required. Due to the similarities of SARS-CoV-2 with the original SARS-CoV, several laboratories are focusing on the viral genome structural proteins like spike glycoprotein (S), a small envelope protein (E), matrix glycoprotein (M), nucleocapsid protein (N) [6,7], the 3CLpro, the main protease required for the maturation of coronaviruses, the protease polymerase (RdRp) is vital for the viral life cycle, making it an attractive target of anti-coronavirus drug development. ...
Background: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone- dependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative. Objective: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents. Methods: Pregnenolone (1) was converted to 3β-hydroxy-21-hydroxymethylidenepregn-5-en-20-one (2) which upon cyclization with phenylhydrazine generated regioisomeric pairs of pyrazoles 4 and 5. Further, Knoevenagel condensation of pregnenolone (1) with 3-oxo-3-phenylpropanenitrile (6) produced 2-benzoyl-3-(3-hydroxy-androstan-5-ene-20-ylidene)-but-2-enenitrile (7) which upon cyclization with hydrazine or phenylhydrazine generated the pyrazoles 8 and 9. All new steroidal derivatives were tested for their aromatase inhibition activity using dibenzylfluorescein (DBF) based florescence assay developed by Stresser et al. Antiproliferative activities were measured using Sulforhodamine B assay. The activities were promising and there was coherence between aromatase inhibitory and antiproliferative activities. Results: The study reveals the immense potential of pregnenolone pyrazoles as aromatase inhibitors for treatment of breast cancer. Molecular docking studies prove efficient binding of the new steroidal analogs on human placental aromatase. Conclusions: In the overall study, most of the compounds exhibited potential activity for treatment of hormone dependent breast cancer. Compounds 4c and 4d were found to be the most promising pharmacons. Furthermore, compound 4c and 4d were applied for their molecular docking study on human placental aromatase to predict their possible binding modes with the enzyme. These studies revealed that such molecules have high scope and potential for further investigation towards treatment of estrogen dependent breast cancer.
... This makes it the most attractive target for the development of anticoronavirus drugs in addition to four structural proteins (i.e. nucleocapsid protein N, matrix glycoprotein M, envelope protein E, spike glycoprotein S) [27][28][29]. Therefore, the atomistic structure of 3CL hydrolase of SARS-CoV-2 is established to investigate interaction mechanism with the biocidal ingredients, being presented in Figure 1(a). ...
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Exploring effective disinfection methods and understanding their mechanisms on the new coronavirus is becoming more active due to the outbreak of novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). By combining molecular dynamics and first-principles calculations, we investigate the interaction mechanism of chemical agents with 3CL hydrolase of SARS-CoV-2. The radial distribution functions indicate that the biocidal ingredients are sensitive to the unsaturated oxygen atoms of 3CL hydrolase and their interactions remarkably depend on the concentration of the biocidal ingredients. Besides, we find that the adsorption performance of the active ingredients for the unsaturated oxygen atoms is superior to other styles of atoms. These computational results not only decipher the inactivation mechanism of chemical agents against SARS-CoV-2 from the molecule-level perspective, but also provide a theoretical basis for the development and application of new chemical methods with a high disinfection efficiency.
... The coronavirus-2 or SARS-CoV-2 genome translates four structural proteins namely small envelope protein (E), spike glycoprotein (S), matrix glycoprotein (M), and nucleocapsid protein (N) [Reddy et. al. 2003]. Over and above the four structural genes, two proteases: (i) papain-like protease (PLP) and (ii) 3-Chymotrypsin-Like protease (3CLpro) or the main (M pro ) protease required for the maturation of coronaviruses, which co-translationally cleaves the two polypeptides into mature non-structural proteins (NSPs) [Lim et. al. 2000] that is c ...
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Coronavirus-2 Main protease (SARS-CoV-2 M<sup>pro</sup>), one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and a crucial target for drug discovery, has been battered with numerous types of drugs/inhibitors. Regrettably, till date there is no any potential drugs or effective inhibitors available to combat its action. Based on the reports of HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M<sup>pro</sup>, we have chosen few clinically trialed experimental HIV-protease inhibitors (JE-2147, KNI-227 and KNI-272) and a variant JE2-CH3, to examine their binding affinities with SARS-CoV-2 M<sup>pro</sup> and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the rational elucidation of the binding mechanism of these four inhibitors to SARS-CoV-2 M<sup>pro</sup> by merging molecular docking, Molecular Dynamics (MD) simulation, and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (-14.95 kcal/mol) compared to JE2-CH3 (--11.19 kcal/mol), KNI-227 (-13.93 kcal/mol) and KNI-272 (-12.84 kcal/mol) against SARS-CoV-2 M<sup>pro</sup>. The increase in binding affinity for JE-2147 comparative to other three inhibitors arises due to an increased favorable van der Waals interactions and decreased solvation energies between the inhibitor and viral protease. Residue decomposition analysis and hydrogen bonding pattern confirms binding affinities of the inhibitors crucial for the interactions. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Pro168, Gln189 etc.) from the active site or near the active site regions with more than 1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 M<sup>pro</sup> drugs. <br
... A number of pharmaceuticals already being tested [3][4][5], but a better understanding of the underlying pathobiology is required. Due to the similarities of SARS-CoV-2 with the original SARS-CoV, several laboratories are focusing on the viral genome structural proteins like spike glycoprotein (S), a small envelope protein (E), matrix glycoprotein (M), nucleocapsid protein (N) [6,7], the 3CLpro, the main protease required for the maturation of coronaviruses, the protease polymerase (RdRp) is vital for the viral life cycle, making it an attractive target of anti-coronavirus drug development. ...
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The rapid spread of the novel coronavirus (SARS-CoV-2) as a serious threat to the world public health is in dire need of finding potential therapeutic agents. Chinese have tested several antiviral and antimalarial drugs as potent inhibitors for the novel virus, such as remdesivir, chloroquine, hydroxychloroquine, umifenovir and favipiravir. In this study, we used the molecular docking models to study the binding interactions between these pharmaceuticals, as well as our proposed remdesivir analogue (AZCV-20) with the 3CLpro and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2, using MEO and Autodock4 methods. Our study provides insight into the possible role of structural flexibility and efficacy during interactions between 3CLpro, RdRp and the drugs.
... SARS-CoV-2 has been identied as the seventh member of the coronavirus family. 1 Through whole genome sequence alignment analysis, SARS-CoV-2 was found to have higher sequence homology toward SARS-CoV-1, which caused the SARS outbreak in 2003. 2 The coronavirus genome encodes four structural proteins: spike glycoprotein (S), small envelope protein (E), matrix glycoprotein (M) and nucleocapsid protein (N). 3 In addition to these four structural genes, 3CLproa main protease required for coronavirus maturationis vital for the viral life cycle, making it an attractive target of anti-coronavirus drug development. [4][5][6] By sequence alignment, it has been found that SARS-CoV-2 3CLpro (3CLpro-2) and SARS-CoV-1 3CLpro (3CLpro-1) share remarkable 96% sequence identity (Fig. 1A). ...
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A novel severe acute respiratory syndrome human coronavirus (SARS HCoV) was identified from respiratory illness patients (named SARS-CoV-2 by ICTV) in December 2019 and has recently emerged as a serious threat to world public health. However, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that HIV protease inhibitors can be used as anti-SARS drugs by targeting SARS-CoV-1 3CLpro, we chose six approved anti-HIV drugs and investigated their binding interactions with 3CLpro to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID-19) caused by SARS-CoV-2 infection. The molecular docking results indicate that the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than does SARS-CoV-1. Two docking complexes (indinavir and darunavir) with high docking scores were further subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two protease inhibitors and SARS HCoV 3CLpro. Our results show that, among the inhibitors tested, darunavir has the highest binding affinity with SARS-CoV-2 and SARS-CoV-1 3CLpro, indicating that it may have the potential to be used as an anti-COVID-19 clinical drug. The mechanism behind the increased binding affinity of HIV protease inhibitors toward SARS-CoV-2 3CLpro (as compared to SARS-CoV-1) was investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between SARS HCoV 3CLpro and inhibitors and sheds light on structure-based design of anti-COVID-19 drugs targeting SARS-CoV-2 3CLpro.
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Protein folding is a fundamental problem in life sciences. It is generally known that nonlocal interactions determine the folding conformation to the context of the folding process. 1,2 As the most common regular secondary conformation in proteins, the helix has been an important ingredient of the protein folding problem. 3 In particular alanine-based polypeptides are widely studied to identify the helix-folding process in that the alanine amino acid is known to have one of the highest helix propensities. In principle, intrinsic helix propensities can be obtained from gas-phase measurements where the solvent effect is absent. Hudgins et al. studied alanine-based peptides in vacuo using the high-resolution ion mobility measurement technique. 4 It was reported that introduction of a single lysine at the C terminus (to form Ac-A n -LysH +) resulted in the formation of very stable, monomeric polyalanine helices. 5 Here, we have investigated (using ab initio calculation and simulaton approach) the helix formation in vacuo in different terminal charge conditions from those of Hudgins et al. 5 Then we have found a new type of helix motif. To the best of our knowledge, this type of helix conformation (to be named λ-helix) has not been characterized before. It has been reported that ab initio calculations and simulations can produce helical structures with use of alanine-based se-quences. 6 Further, a recent computation study showed that proteins with other amino acid sequences can be designed to adopt the desired structures. 7 We have carried out ab initio calculations (Gaussian 98) 8 and molecular dynamics (MD) simulations (CHARMm 9 V26 with the CHARMM22 parameter set 10) of alanine-based polypeptides. Two terminal conditions are inves-tigated: H 3 N + -RH-CO-[NH-RH-CO] n-2 -NH-RH-COO -(NH 3 + -A n -COO -in short) and H 3 CCO-[NH-RH-CO] n -NH 2 (CH 3 -A n -NH 2 in short). While the R-helices are observed in the latter case, the unusually stable λ-helix formation is observed in the former case. This left-handed λ-helix (λ L -helix or 6 19 -helix) is shown together with a right-handed R-helix (R R helix) in Figure 1. 11 A Ramachandran plot to represent various protein secondary structures is given in Figure 2. The λ L -helix has five residues per turn with H-bonds between NH of residue n and C′dO of residue n + 4. A right-handed λ-helix is, however, not observed in our simulations due to the close approach of the side chains and the C′O group of L amino acids (as the left-handed R-helix is not observed in the experiments). Our ab initio and simulation results show that the λ L -helix is lower in energy than the R R -helix when both ends are charged (Table 1). The Becke-3 parameters with Lee-Yang-Parr func-tionals (B3LYP) using the 6-31G* basis set show that the λ L -helix with charged ends (NH 3 + -A n -COO -) is more stable than the neutral R R -helix (NH 2 -A n -COOH) by ∼2 kcal/mol for n) 8, which implies that the zwitterionic λ L -helix can exist in the gas phase as a global or at least a local minimum energy structure. The existence of λ L -helix is ensured from the all-positive
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Jones, S. J. M.; Astell, C. R.; Holt, R. A.; Wilson, A. B. et al., Science 2003, 300, 1399. (c) Anand, K.; Zeibuhr, J.; Wadhwani, P.; Mesters, J. R.; Hilgenfeld, R. Science 2003, 300, 1763.