SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations

Tumskiy, Roman S.; Tumskaia, Anastasiia V.; Klochkova, Iraida Nikolaevna; Richardson, Rudy J.

doi:10.1016/j.compbiomed.2022.106449

Cited by 20 publications

(22 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in the case of 6Y84, we notice a major structural alteration in the loop adjoining domains I and II and the helical domain III (Figure 5E), which signifies that M PRO can exist in multiple conformations with or without ligands. These quantitative results perfectly substantiate with the earlier studies using equivalent MD setup 77 …”

Section: Resultssupporting

confidence: 91%

“…These quantitative results perfectly substantiate with the earlier studies using equivalent MD setup. 77 Studies have confirmed that the inhibiting power of a compound can be modulated by its capability to form covalent bonds with Cys145. 23 Therefore, to understand the conformational changes in the catalytic site, we superimposed the experimental as well as MD simulated structures (Figure 6).…”

Section: Conformational States Of Sars-cov-2 M Promentioning

confidence: 97%

See 1 more Smart Citation

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Dehury

Mishra

2023

J of Cellular Biochemistry

View full text Add to dashboard Cite

The spread of different severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants underscores the need for insights into the structural properties of its structural and non‐structural proteins. The highly conserved homo‐dimeric chymotrypsin‐like protease (3CL MPRO), belonging to the class of cysteine hydrolases, plays an indispensable role in processing viral polyproteins that are involved in viral replication and transcription. Studies have successfully demonstrated the role of MPRO as an attractive drug target for designing antiviral treatments because of its importance in the viral life cycle. Herein, we report the structural dynamics of six experimentally solved structures of MPRO (i.e., 6LU7, 6M03, 6WQF, 6Y2E, 6Y84, and 7BUY including both ligand‐free and ligand‐bound states) at different resolutions. We have employed a structure‐based balanced forcefield, CHARMM36m through state‐of‐the‐art all‐atoms molecular dynamics simulations at µ‐seconds scale at room temperature (303K) and pH 7.0 to explore their structure‐function relationship. The helical domain‐III responsible for dimerization mostly contributes to the altered conformational states and destabilization of MPRO. A keen observation of the high degree of flexibility in the P5 binding pocket adjoining domain II‐III highlights the reason for observation of conformational heterogeneity among the structural ensembles of MPRO. We also observe a differential dynamics of the catalytic pocket residues His41, Cys145, and Asp187, which may lead to catalytic impairment of the monomeric proteases. Among the highly populated conformational states of the six systems, 6LU7 and 7M03 forms the most stable and compact MPRO conformation with intact catalytic site and structural integrity. Altogether, our findings from this extensive study provides a benchmark to identify physiologically relevant structures of such promising drug targets for structure‐based drug design and discovery of potent drug‐like compounds having clinical potential.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Conformational States Of Sars-cov-2 M Promentioning

confidence: 97%

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Dehury

Mishra

2023

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…This has motivated continuous efforts to look for adequate inhibitors of the protease to be used as potential drugs, using both experimental [8][9][10][11][12][13][14] and computational approaches. [15][16][17][18][19] Many of these compounds are covalent inhibitors that contain an electrophilic site able to react with the catalytic cysteine of 3CL pro , Cys145, mimicking the behavior of the peptidic substrate. Covalent inhibitors rst bind into the active site of the protease forming a non-covalent complex (EI) and then react with Cys145 to form a covalent complex (E-I):…”

Section: Introductionmentioning

confidence: 99%

The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Recently researchers used some techniques to predict the drug ability of hit compounds such as the Lipinski rule of 5 (Ro5) and the ADME/T parameters 41 . Three parameters of Ro5 including molecular weight, hydrogen bond acceptor, and hydrogen bond donor, are related to the interaction of the ligands and the active site of the protein.…”

Section: Resultsmentioning

confidence: 99%

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

Zare,

Ataollahi,

Mardaneh

et al. 2024

Sci Rep

View full text Add to dashboard Cite

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand–protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

show abstract

SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations

Cited by 20 publications

References 82 publications

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

Contact Info

Product

Resources

About