Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations

Singh, Rahul; Bhardwaj, Vijay Kumar; Das, Pralay; Bhattacherjee, Dhananjay; Zyryanov, Grigory V.; Purohit, Rituraj

doi:10.1016/j.compbiomed.2022.105572

Cited by 32 publications

(22 citation statements)

References 53 publications

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“…The interaction energy indicates the strength of a protein–ligand complex. This was validated by estimating the binding free energy using the MM-PBSA approach ( Singh et al, 2022 ). The MD trajectories of the 10-ns range were used to predict the binding free energy of complexes.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we wanted to identify a natural compound that binds and inhibits the proteins of SARS-CoV-2 and thereby prevents the virus. There are several in silico studies which propose potential inhibitors from diverse sources against distinct proteins of SARS-CoV-2 by using docking and simulations ( Bhardwaj et al, 2021 ; Sharma et al, 2021 ; Singh et al, 2022 ). In this study, we screened a set of ∼1.8 lakh natural compounds to target Orf1ab of SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

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In silico prediction of the animal susceptibility and virtual screening of natural compounds against SARS-CoV-2: Molecular dynamics simulation based analysis

et al. 2022

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COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. It has six open reading frames (orf1ab, orf3a, orf6, orf7a, orf8, and orf10), a spike protein, a membrane protein, an envelope small membrane protein, and a nucleocapsid protein, out of which, orf1ab is the largest ORF coding different important non-structural proteins. In this study, an effort was made to evaluate the susceptibility of different animals against SARS-CoV-2 by analyzing the interactions of Spike and ACE2 proteins of the animals and propose a list of potential natural compounds binding to orf1ab of SARS-CoV-2. Here, we analyzed structural interactions between spike proteins of SARS-CoV-2 and the ACE2 receptor of 16 different hosts. A simulation for 50 ns was performed on these complexes. Based on post-simulation analysis, Chelonia mydas was found to have a more stable complex, while Bubalus bubalis, Aquila chrysaetos chrysaetos, Crocodylus porosus, and Loxodonta africana were found to have the least stable complexes with more fluctuations than all other organisms. Apart from that, we performed domain assignment of orf1ab of SARS-CoV-2 and identified 14 distinct domains. Out of these, Domain 3 (DNA/RNA polymerases) was selected as a target, as it showed no similarities with host proteomes and was validated in silico. Then, the top 10 molecules were selected from the virtual screening of ∼1.8 lakh molecules from the ZINC database, based on binding energy, and validated for ADME and toxicological properties. Three molecules were selected and analyzed further. The structural analysis showed that these molecules were residing within the pocket of the receptor. Finally, a simulation for 200 ns was performed on complexes with three selected molecules. Based on post-simulation analysis (RMSD, RMSF, Rg, SASA, and energies), the molecule ZINC000103666966 was found as the most suitable inhibitory compound against Domain 3. As this is an in silico prediction, further experimental studies could unravel the potential of the proposed molecule against SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In silico prediction of the animal susceptibility and virtual screening of natural compounds against SARS-CoV-2: Molecular dynamics simulation based analysis

et al. 2022

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“…They have tested these peptides experimentally and showed successful viral neutralization. Another such study identifies the potential of Nsp1 inhibitors to promote the complete cessation of host protein translation by aminoarylbenzosuberene molecules (Singh et al 2021a ). Such studies showed that in-silico lead candidates have potential efficacy, and experimental results align with in-silico results for many cases (Singh et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of antiviral peptide inhibitors for receptor binding domain of SARS-CoV-2 omicron and its sub-variants: an in-silico approach

et al. 2022

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Omicron, a variant of concern (VOC) of SARS-CoV-2, emerged in South Africa in November 2021. Omicron has been continuously acquiring a series of new mutations, especially in the spike (S) protein that led to high infectivity and transmissibility. Peptides targeting the receptor-binding domain (RBD) of the spike protein by which omicron and its variants attach to the host receptor, angiotensin-converting enzyme (ACE2) can block the viral infection at the first step. This study aims to identify antiviral peptides from the Antiviral peptide database (AVPdb) and HIV-inhibitory peptide database (HIPdb) against the RBD of omicron by using a molecular docking approach. The lead RBD binder peptides obtained through molecular docking were screened for allergenicity and physicochemical criteria (isoelectric point (pI) and net charge) required for peptide-based drugs. The binding affinity of the best five peptide inhibitors with the RBD of omicron was validated further by molecular dynamics (MD) simulation. Our result introduces five antiviral peptides, including AVP1056, AVP1059, AVP1225, AVP1801, and HIP755, that may effectively hinder omicron-host interactions. It is worth mentioning that all the three major sub-variants of omicron, BA.1 (B.1.1.529.1), BA.2 (B.1.1.529.2), and BA.3 (B.1.1.529.3), exhibits conserved ACE-2 interacting residues. Hence, the screened antiviral peptides with similar affinity can also interrupt the RBD-mediated invasion of different major sub-variants of omicron. Altogether, these peptides can be considered in the peptide-based therapeutics development for omicron treatment after further experimentation. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-022-03258-4.

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“…It catalyzes the polyprotein's translation from viral RNA and specifies a particular cleavage site. Due to the absence of identical cleavage specificity in human cell proteases, targeting Mpro with a chemical compound (synthesized 3 h) can obstruct the replication of the virus [26]. The in silico work is developed with this in mind to evaluate the medicinal potentials of major phytochemicals in N. sativa.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Profile of Nigella sativa Seeds in Combating COVID-19 through In-Vitro and Molecular Docking Studies

et al. 2022

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COVID-19 infection is associated with elevated oxidative stress, systemic hyper-inflammatory responses, endothelial dysfunction, and red blood cell membrane deformability. Nigella sativa extract is widely used in alternative and complementary medicine systems in a large population, due to its highly therapeutic, economic, natural, and safe nature. The aim of this study was to evaluate the effect of N. sativa extract on oxidative stress, hemolysis, proteolysis, and glycation through in vitro studies, as well as to find out its anti-viral potential against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) using in silico studies. N. sativa seed extract (at 600 µg/mL) displayed 67.33% scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test, and 70.28% hydrogen peroxide reducing activity. N. sativa exhibited anti-proteolytic activity by decreasing heat-induced denaturation of bovine serum albumin (BSA) and egg albumin by 63.14% and 57.95%, respectively, and exhibited anti-proteinase potential of 66.28% at 600 μg/mL. In addition, heat-induced hemolysis and hypersalinity-induced hemolysis were inhibited by 57.86% and 61.7%, respectively, by the N. sativa seeds. N. sativa also inhibited browning intensity by 56.38%, and percent aggregation index by 51.38%, amyloid structure by 48.28%, and AGE-specific fluorescence by 52.18%, thereby protecting the native structure of BSA from glycation. The binding interactions between bioactive molecules of N. sativa seed with SARS-CoV-2 spike glycoprotein were proven by using in silico molecular docking tools. The functional amino acids involved in the interactions are Asp467, Thr108, Thr114, Ile468, Asn234, Gln155, Glu465, Arg466, Gly232, and Ile233, indicating the inhibiting property of N. sativa on SARS-CoV-2. Finally, we may infer that phytoconstituents of N. sativa seeds have the potential to protect against the spike protein of SARS-CoV-2. Studies on N. sativa seeds might act as a path to develop a potent alternative therapy against viral infections, especially COVID-19 infection, in the future. However, the limitations linked with the use of natural products are also needed to be considered in this regard.

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Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations

Cited by 32 publications

References 53 publications

In silico prediction of the animal susceptibility and virtual screening of natural compounds against SARS-CoV-2: Molecular dynamics simulation based analysis

In silico prediction of the animal susceptibility and virtual screening of natural compounds against SARS-CoV-2: Molecular dynamics simulation based analysis

Identification of antiviral peptide inhibitors for receptor binding domain of SARS-CoV-2 omicron and its sub-variants: an in-silico approach

Pharmacological Profile of Nigella sativa Seeds in Combating COVID-19 through In-Vitro and Molecular Docking Studies

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