Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease

Mirza, Muhammad Usman; Ahmad, Sarfraz; Abdullah, Iskandar; Froeyen, Matheus

doi:10.1016/j.compbiolchem.2020.107376

Cited by 33 publications

(32 citation statements)

References 76 publications

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“…MD simulation of 50 ns was performed at 300 K and 1 atm for two fs under the NPT ensemble. Hydrogen and covalent bonds were constrained using the SHAKE algorithm [ 83 ], whereas system temperature was controlled through Langevin dynamics [ 84 ]. The initial structure was used as a reference, and CPPTRAJ [ 85 ] of AMBER was run to generate a root-mean-square deviation (RMSD) plot to check the system MD simulation convergence [ 81 ].…”

Section: Methodsmentioning

confidence: 99%

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

et al. 2021

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SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

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Section: Methodsmentioning

confidence: 99%

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

et al. 2021

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“…Representations in the above equations are: ΔG bind = binding energy; - T Δ S = entropic energy; ΔE MM = molecular mechanics potential energy [van der Waals (ΔE vdw ) energy + electrostatic (ΔE elec )]; ΔG sol = solvation free energy [polar solvation energy (ΔE polar ) + non-polar solvation energy (ΔE SASA ). MM/PBSA analysis has been widely used in binding free energy calculations for anti-viral inhibitors [ 32 , [49] , [50] , [51] , [52] , [53] , [54] , [55] ].…”

Section: Methodsmentioning

confidence: 99%

Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation

Alamri

Qamar

Afzal

et al. 2021

Journal of Molecular Liquids

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Middle east respiratory syndrome coronavirus (MERS-CoV) is a fatal pathogen that poses a serious health risk worldwide and especially in the middle east countries. Targeting the MERS-CoV 3-chymotrypsin-like cysteine protease (3CL pro ) with small covalent inhibitors is a significant approach to inhibit replication of the virus. The present work includes generating a pharmacophore model based on the X-ray crystal structures of MERS-CoV 3CL pro in complex with two covalently bound inhibitors. In silico screening of covalent chemical database having 31,642 compounds led to the identification of 378 compounds that fulfils the pharmacophore queries. Lipinski rules of five were then applied to select only compounds with the best physiochemical properties for orally bioavailable drugs. 260 compounds were obtained and subjected to covalent docking-based virtual screening to determine their binding energy scores. The top three candidate compounds, which were shown to adapt similar binding modes as the reported covalent ligands were selected. The mechanism and stability of binding of these compounds were confirmed by 100 ns molecular dynamic simulation followed by MM/PBSA binding free energy calculation. The identified compounds can facilitate the rational design of novel covalent inhibitors of MERS-CoV 3CL pro enzyme as anti-MERS CoV drugs.

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“…From this perspective, further studies using Usp2 KO mice or specific USP2 inhibitors may be useful for the functional validation of the roles of USP2 in vivo. Meanwhile, drug specificity should be taken into consideration, because many chemical inhibitors have unexpected molecular targets [ 159 ]; for example, a recent paper reported that a USP2 blocker also inhibits severe acute respiratory syndrome coronavirus 2 papain-like protease [ 160 ]. Considering that these inhibitors can affect enzymes with similar structures, chemical inhibitors of USP2 could perturb other endogenous proteins.…”

Section: Perspectivesmentioning

confidence: 99%

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Kitamura

Hashimoto

2021

IJMS

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Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

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Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease

Abstract: Graphical abstract

Cited by 33 publications

References 76 publications

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

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