Computational Studies of the Mechanism of Catalysis and Inhibition of Cysteine Proteases

Cruz, Kemel Arafet

doi:10.6035/14026.2017.384574

Cited by 1 publication

(1 citation statement)

References 147 publications

(187 reference statements)

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“…However, it does not affect the activity of cathepsin cysteinase in mammals [ 20 ]. Combining the crystal structure of the complex of E64 molecule and cysteine enzyme and previous studies on E64 molecule and its analogues [ 21 , 22 , 23 , 24 , 25 , 26 ], we hypothesized that C2 epoxide group of E64 reacts with the thiol group of cysteine through electrophilic attack, leading to the formation of a covalent bond with the catalytic triad of cysteine. This bond irreversibly inactivates the hydrolytic activity of the cysteine protease.…”

Section: Introductionmentioning

confidence: 99%

The Structural Basis of African Swine Fever Virus pS273R Protease Binding to E64 through Molecular Dynamics Simulations

Liu

Jing

et al. 2023

Molecules

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Identification of novel drugs for anti-African swine fever (ASF) applications is of utmost urgency, as it negatively affects pig farming and no effective vaccine or treatment is currently available. African swine fever virus (ASFV) encoded pS273R is a cysteine protease that plays an important role in virus replication. E64, acting as an inhibitor of cysteine protease, has been established as exerting an inhibitory effect on pS273R. In order to obtain a better understanding of the interaction between E64 and pS273R, common docking, restriction docking, and covalent docking were employed to analyze the optimal bonding position between pS273R−E64 and its bonding strength. Additionally, three sets of 100 ns molecular dynamics simulations were conducted to examine the conformational dynamics of pS273R and the dynamic interaction of pS273R−E64, based on a variety of analytical methods including root mean square deviation (RMSD), root mean square fluctuation (RMSF), free energy of ligand (FEL), principal component analysis (PCA), and molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis. The results show that E64 and pS273R exhibited close binding degrees at the activity center of ASFV pS273R protease. The data of these simulations indicate that binding of E64 to pS273R results in a reduction in flexibility, particularly in the ARM region, and a change in the conformational space of pS273R. Additionally, the ability of E64 to interact with polar amino acids such as ASN158, SER192, and GLN229, as well as charged amino acids such as LYS167 and HIS168, seems to be an important factor in its inhibitory effect. Finally, Octet biostratigraphy confirmed the binding of E64 and pS273R with a KD value of 903 uM. Overall, these findings could potentially be utilized in the development of novel inhibitors of pS273R to address the challenges posed by ASFV.

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