Targeting viral proteins for restraining SARS-CoV-2: focusing lens on viral proteins beyond spike for discovering new drug targets

Expert Opinion on Drug Discovery, Journal Year: 2023, Volume and Issue: 18(3), P. 247 - 268

Published: Feb. 1, 2023

Introduction Emergence of highly infectious SARS-CoV-2 variants are reducing protection provided by current vaccines, requiring constant updates in antiviral approaches. The virus encodes four structural and sixteen nonstructural proteins which play important roles viral genome replication transcription, virion assembly, release , entry into cells, compromising host cellular defenses. As alien to many represent potential targets for combating the SARS-CoV-2.Areas covered Based on literature from PubMed Web Science databases, authors summarize typical characteristics whole particle individual their corresponding functions life cycle. also discuss emerging targeted interventions curb spread detail provide unique insights infection countermeasures against it.Expert opinion Our comprehensive analysis highlights rationale focus non-spike that less mutated but have functions. Examples this include: (e.g. nucleocapsid protein, envelope protein) extensively-concerned NSP3, NSP5, NSP12) along with ones relatively attention NSP1, NSP10, NSP14 NSP16), developing novel drugs overcome resistance preexisting vaccines antibody-based treatments.

Language: Английский

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In-silico study: docking simulation and molecular dynamics of peptidomimetic fullerene-based derivatives against SARS-CoV-2 Mpro

3 Biotech, Journal Year: 2023, Volume and Issue: 13(6)

Published: May 13, 2023

Language: Английский

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Assessing the Potential Contribution of in Silico Studies in Discovering Drug Candidates that Interact with Various SARS-CoV-2 Receptors

Published: Aug. 4, 2023

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly search candidates that interact with various SARS-CoV-2 receptors. These involve use of computer simulations and computational algorithms predict potential interaction target The primary receptors targeted by include RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, AP2-associated protein kinase 1. identified several promising candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, Camostat mesylate, among others. offers advantages, ability screen large number relatively short amount time, thereby reducing time cost involved traditional methods. Additionally, allow prediction binding affinity receptors, providing insight into their efficacy. However, it is crucial consider both advantages limitations these complement them experimental validation ensure efficacy safety candidates.

Language: Английский

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Triterpene Derivatives as Potential Inhibitors of the RBD Spike Protein from SARS-CoV-2: An In Silico Approach

Molecules, Journal Year: 2023, Volume and Issue: 28(5), P. 2333 - 2333

Published: March 2, 2023

The appearance of a new coronavirus, SARS-CoV-2, in 2019 kicked off an international public health emergency. Although rapid progress vaccination has reduced the number deaths, development alternative treatments to overcome disease is still necessary. It known that infection begins with interaction spike glycoprotein (at virus surface) and angiotensin-converting enzyme 2 cell receptor (ACE2). Therefore, straightforward solution for promoting inhibition seems be search molecules capable abolishing such attachment. In this work, we tested 18 triterpene derivatives as potential inhibitors SARS-CoV-2 against receptor-binding domain (RBD) protein by means molecular docking dynamics simulations, modeling RBD S1 subunit from X-ray structure RBD-ACE2 complex (PDB ID: 6M0J). Molecular revealed at least three each type (i.e., oleanolic, moronic ursolic) present similar energies reference molecule, i.e., glycyrrhizic acid. suggest two compounds oleanolic ursolic acid, OA5 UA2, can induce conformational changes disrupting interaction. Finally, physicochemical pharmacokinetic properties simulations favorable biological activity antivirals.

Language: Английский

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Discovery of Chalcone-Based Hybrid Structures as High Affinity and Site-Specific Inhibitors against SARS-CoV-2: A Comprehensive Structural Analysis Based on Various Host-Based and Viral Targets

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8789 - 8789

Published: May 15, 2023

Previous studies indicated that natural-based chalcones have significant inhibitory effects on the coronavirus enzymes 3CLpro and PLpro as well modulation of some host-based antiviral targets (HBATs). In this study, a comprehensive computational structural study was performed to investigate affinity our compound library consisting 757 chalcone-based structures (CHA-1 CHA-757) for inhibiting against twelve selected targets. Our results CHA-12 (VUF 4819) is most potent multi-target inhibitor in chemical over all viral Correspondingly, CHA-384 its congeners containing ureide moieties were found be selective inhibitors, benzotriazole moiety CHA-37 main fragment PLpro. Surprisingly, indicate sulfonamide are integral fragments optimum inhibition while occupying S1 S3 subsites, which fully consistent with recent reports site-specific inhibitors. Finding CHA-12, previously reported an LTD4 antagonist treatment inflammatory pulmonary diseases, prompted us suggest it concomitant agent relieving respiratory symptoms suppressing COVID-19 infection.

Language: Английский

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Repurposing and computational design of PARP inhibitors as SARS-CoV-2 inhibitors

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: June 29, 2023

Coronavirus disease 2019 (COVID-19) is a recent pandemic that caused serious global emergency. To identify new and effective therapeutics, we employed drug repurposing approach. The poly (ADP ribose) polymerase inhibitors were used for this purpose repurposed against the main protease (Mpro) target of severe acute respiratory syndrome 2 (SARS-CoV-2). results from these studies to design compounds using 'Grow Scaffold' modules available on Discovery Studio v2018. three designed compounds, olaparib 1826 1885, rucaparib 184 demonstrated better CDOCKER docking scores Mpro than their parent compounds. Moreover, adhered Lipinski's rule five synthetic accessibility score 3.55, 3.63, 4.30 1826, 184, respectively. short-range Coulombic Lennard-Jones potentials also support potential binding modified Mpro. Therefore, propose as novel SARS-CoV-2 inhibitors.

Language: Английский

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Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 11

Published: Nov. 18, 2023

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents substantial threat to health, especially in nations. Given no FDA-approved specific therapy for MERS exists, designing and discovering potent antiviral MERS-CoV crucial. One pivotal strategy inhibiting replication focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting cherry-picked molecules from literature. key features URDL include synthetic tractability (1-2 pot synthesis) scaffold unexplored chemical space. hits were ranked based docking score, MM-GBSA free energy binding, interaction pattern with active site residues. A molecular dynamics (MD) simulation study was performed first two top-ranked compounds analyze stability binding mechanics Poisson-Boltzmann surface area. mean force calculated steered (SMD) simulations indicates improved H-bond potential, enhanced conformational stability, affinity toward target, compared cocrystallized ligand. discovered represent synthetically tractable scaffolds as inhibitors.Communicated by Ramaswamy H. Sarma.

Language: Английский

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

Processes, Journal Year: 2022, Volume and Issue: 10(7), P. 1346 - 1346

Published: July 11, 2022

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

Language: Английский

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Characterizing the ligand-binding affinity toward SARS-CoV-2 Mproviaphysics- and knowledge-based approaches

Physical Chemistry Chemical Physics, Journal Year: 2022, Volume and Issue: 24(48), P. 29266 - 29278

Published: Jan. 1, 2022

Computational approaches, including physics- and knowledge-based methods, have commonly been used to determine the ligand-binding affinity toward SARS-CoV-2 main protease (Mpro or 3CLpro).

Language: Английский

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Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay

International Journal of Biological Macromolecules, Journal Year: 2022, Volume and Issue: 226, P. 780 - 792

Published: Dec. 12, 2022

Language: Английский

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