Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Douangamath, A.; Fearon, D.; Gehrtz, P.; Krojer, T.; Lukacik, P.; Owen, C.D.; Resnick, E.; Strain-Damerell, Claire; Aimon, A.; Ábrányi‐Balogh, Péter; Brandão-Neto, J.; Carbery, A.; Davison, Gemma; Dias, A.; Downes, Thomas D.; Dunnett, L.; Fairhead, M.; Firth, James D.; Jones, Simon P.; Keely, Aaron; Keserü, György M.; Klein, Hanna F.; Martin, Mathew P.; Noble, M.E.M.; O’Brien, Peter; Powell, A.J.; Reddi, Rambabu N.; Skyner, R.; Snee, M.; Waring, Michael J.; Wild, C.; London, Nir; Delft, F. von; Walsh, Martin A.

doi:10.1101/2020.05.27.118117

Cited by 47 publications

(63 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7,8 These inhibitor-bound structures provide excellent starting points for further drug optimization strategies. In addition to the crystal structures of M pro , both in its apo as well as ligand-bound states, 7,8,11 recent crystallographic screening 16 has revealed the binding of a multitude of molecular fragments both in the active site as well as at the dimer interface where oligomerization can be disrupted. Such structural studies, complemented by computational tools for drug design, offer tremendous promise for the rapid generation of potent lead compounds for the production of effective antivirals.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Pavlova

Lynch

Daidone

et al. 2020

Preprint

View full text Add to dashboard Cite

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored Nδ (HD) and Nϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Pavlova

Lynch

Daidone

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Among the 50 known non-covallently bound fragments inside the active site, 11 we selected three ligands JFM, U0P and HWH ( Fig. 1a) that bind the active site at different locations (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…10 Besides the covallently bound ligands, dozens of noncovallently bound drug fragments that span the entire active site of the SARS-CoV-2 Mpro have also been identified using large crystallographic and mass-spectrometry screening. 11 These structures (listed on COVID Moonshot website and deposited in Protein Data Bank) reveal an exceptionally rich set of information, with extensive opportunities for fragment-based drug discovery (FBDD) for inhibiting the SARS-CoV-2 Mpro.…”

Section: Introductionmentioning

confidence: 99%

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

Luan

Huynh

2020

Preprint

View full text Add to dashboard Cite

Since the beginning of the COVID-19 pandemic, researchers and scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS-CoV-2 virus. Despite many promising ongoing progress, there are currently no FDA approved drugs to treat infected patients. Among the various protein targets of SARS-CoV-2 virus, the main protease (Mpro) has attracted most interests. Recently, the crowdsourcing of drug discovery for inhibiting Mpro have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment-based drug design (FBDD), we are motivated to design a potent drug molecule through merging several of these newly discovered drug fragments. Among various designed ligands, we found that B19 by merging three fragments JFM, U0P and HWH is the most stable one, evidenced through extensive (~10 μs totally) all-atom molecular dynamics simulation. We further estimated that the binding free energy of B19 is comparable or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 can potentially be an efficacious drug molecule for inhibiting Mpro of SARS-CoV-2.

show abstract

“…For example, a reversible-covalent α-ketoamide inhibitor 46 (biochemical IC50 0.67 µM ± 0.18 µM) probes the S3/4 region with an additional hydrogen bond to the backbone of Glu166. In a large scale fragment screen, numerous fragments were able to bind in these pockets 47 . In this case, we exhaustively synthesized analogs of 10, using 34 available isocyanides.…”

Section: A Covalent Sars-cov-2 Main Protease Inhibitormentioning

confidence: 99%

“…We chose 9 isocyanide replacements and 14 amine replacements (one of them was not based on docking). Most combinations of these components were made by Enamine and tested as part of the Covid-Moonshot effort 47,67 .…”

Section: Computational Optimisation Of the M Pro Inhibitormentioning

confidence: 99%

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^proinhibitor

Zaidman

Gehrtz

Filep

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Designing covalent inhibitors is a task of increasing importance in drug discovery. Efficiently designing irreversible inhibitors, though, remains challenging. Here, we present covalentizer, a computational pipeline for creating irreversible inhibitors based on complex structures of targets with known reversible binders. For each ligand, we create a custom-made focused library of covalent analogs. We use covalent docking, to dock these tailored covalent libraries and to find those that can bind covalently to a nearby cysteine while keeping some of the main interactions of the original molecule. We found ~11,000 cysteines in close proximity to a ligand across 8,386 protein-ligand complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In prospective evaluation against a panel of kinases, five out of nine predicted covalent inhibitors showed IC50 between 155 nM - 4.2 μM. Application of the protocol to an existing SARS-CoV-1 Mpro reversible inhibitor led to a new acrylamide inhibitor series with low micromolar IC50 against SARS-CoV-2 Mpro. The docking prediction was validated by 11 co-crystal structures. This is a promising lead series for COVID-19 antivirals. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.

show abstract

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Cited by 47 publications

References 61 publications

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

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

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^proinhibitor

Contact Info

Product

Resources

About

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Cited by 47 publications

References 61 publications

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

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

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mproinhibitor

Contact Info

Product

Resources

About

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M^proinhibitor