Crystal-Structures-Guided Design of  Fragment-Based Drugs for Inhibiting the Main Protease of SARS-CoV-2

Luan, Binquan; Huynh, Tien

doi:10.21203/rs.3.rs-80869/v1

Cited by 4 publications

(5 citation statements)

References 17 publications

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“…Finally, 17 molecules with binding abilities were found from which 15 molecules form a stable binding. Luan and Huynh, (2020) merged three-drug fragments (JFM, U0P, and HWH) into B19 which showed a slightly better free binding energy than the native peptide cleaved by the M pro .…”

Section: Potential Inhibitors Of Sars-cov-2 M Promentioning

confidence: 99%

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021

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The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

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Section: Potential Inhibitors Of Sars-cov-2 M Promentioning

confidence: 99%

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021

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“…It was hypothesized that using appropriate linkers to join the fragment poses could provide a larger molecule whose divalent binding would encompass the interactions formed by its component domains. This approach has been used before for this protein, but only on a far more limited scale where three co-crystallized fragments were used to design 19 ligands (Luan & Huynh, 2020).…”

Section: Fragment Coupling and Linker Selectionmentioning

confidence: 99%

Fragment‐based in silico design of SARS‐CoV‐2 main protease inhibitors

et al. 2021

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and 579,366 associated deaths had been reported in the United States (https://covid.cdc. gov/covid -data-track er/#cases_cases per10 0klas t7days). It is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Alamri et al., 2020a; Alamri et al., 2020b;. The elderly, and those afflicted with chronic illness or possessing a compromised immune system are more likely to be severely affected (Shah et al., 2020). Virions are readily transmitted through aerosols or droplets adsorbing via the mucous membranes of the eyes, mouth, lungs, and nose (Karia et al., 2020). At this point, the zoological origin of the disease remains uncertain, with competing hypotheses suggesting it might have been

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“…It was hypothesized that using appropriate linkers to join the fragment poses could provide relatively similar poses as constituting fragments. A previous relatively similar but limited study has reported using only three cocrystallized fragments to design 19 ligands [29].…”

Section: Fragment Coupling and Linker Selectionmentioning

confidence: 99%

Extensive Crystallographic Fragment-Based Approach to Design SARS CoV2 3CLpro Main Protease Inhibitors and Related Metadata

Ahmad

Abdullah²,

Lee³

et al. 2021

Preprint

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3CLpro is a vital protein for the SARS-CoV-2 replications and its inhibition using small molecules is a bona fide approach used to develop new drugs against the virus. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. Protein Data Bank was explored to find small molecules cocrystallized with SARS-CoV-2 3CLpro. The fragments sitting in the binding pocket (87) were interactively coupled using various linkers with the intention to get molecules having the same orientation as those of the constituting fragments. In total, 1251 couples were prepared and converted to maximum possible stereoisomers using LigPrep for screening using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. Top 22 hits having conformations similar to their cocrystallized fragments were selected for MD simulation on Desmond. MD simulation suggested that 15 hits had conformations very close to their constituting fragments. Results indicated that these hits were computationally reliable and could be considered for further development. This suggests that the study could provide a benchmark starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding (data provided).

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Crystal-Structures-Guided Design of Fragment-Based Drugs for Inhibiting the Main Protease of SARS-CoV-2

Cited by 4 publications

References 17 publications

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Fragment‐based in silico design of SARS‐CoV‐2 main protease inhibitors

Extensive Crystallographic Fragment-Based Approach to Design SARS CoV2 3CLpro Main Protease Inhibitors and Related Metadata

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