Searching and designing potential inhibitors for SARS-CoV-2 Mpro from natural sources using atomistic and deep-learning calculations

Tâm, Nguyễn Minh; Pham, Duc-Hung; Hiệp, Đinh Minh; Tran, Phuong‐Thao; Quang, Duong Tuan; Ngo, Son Tung

doi:10.1039/d1ra06534c

Cited by 11 publications

(5 citation statements)

References 76 publications

(98 reference statements)

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“…DeepFrag calculations were designed to predict the structural change of the inhibitor that may enhance the ligand-binding affinity [ 34 , 35 ]. In particular, the ML model was successfully applied to the SARS-CoV-2 Mpro + inhibitor [ 38 ]. The ligand-binding affinity was then confirmed via FPL simulations [ 38 ], which revealed a correlation coefficient with the respective experiment of

[ 32 ].…”

Section: Resultsmentioning

confidence: 99%

“…In particular, the ML model was successfully applied to the SARS-CoV-2 Mpro + inhibitor [ 38 ]. The ligand-binding affinity was then confirmed via FPL simulations [ 38 ], which revealed a correlation coefficient with the respective experiment of

[ 32 ]. The hybrid approaches were thus utilized to modify the structure of nirmatrelvir, which may lead to a novel compound forming stronger binding affinity to the protease.…”

Section: Resultsmentioning

confidence: 99%

“…Among these, the inhibitor atoms were designated to estimate that the ligand-binding affinity can be enhanced if they are replaced by another chemical group. A probable modification was kept if the score of the DeepFrag model was larger than 0.90 [ 38 ].

Fig.…”

Section: Methodsmentioning

confidence: 99%

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Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

Tam

Nguyen

Quan

et al. 2023

Journal of Molecular Graphics and Modelling

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[ 32 ].…”

Section: Resultsmentioning

confidence: 99%

[ 32 ]. The hybrid approaches were thus utilized to modify the structure of nirmatrelvir, which may lead to a novel compound forming stronger binding affinity to the protease.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

Tam

Nguyen

Quan

et al. 2023

Journal of Molecular Graphics and Modelling

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“…Streptonigrin tetracyclic aminoquinoline-5,8 dione is an antitumor antibiotic and a previous screening against SARS-CoV-2 nsp15 endoribonuclease identi ed as positive hit [23]. Scillaren A, is a cardiac glycoside derived from Drimia species [24] and in silico studies reported to have SARS CoV-2 Mpro binding a nities [25]. Proscillaridin, is a cardiac glycoside isolated from Drimia maritima, an anticancer drug that inhibits DNA topoisomerase I and II [26].…”

Section: Discussionmentioning

confidence: 99%

A High-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity

Shine

Lupitha

Chandrasekharan

et al. 2023

Preprint

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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to host cell is mediated through the binding of the SARS-CoV-2 Spike protein via receptor binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2). Identifying compounds inhibiting Spike-ACE2 binding would be a promising, safe antiviral approach against COVID-19. Methods: In the present study, we have used BSL-2 compatible replication-competent vesicular stomatitis virus (VSV) replaced glycoprotein with spike protein of SARS-CoV-2 expressing eGFP reporter system (VSV-eGFP-SARS-CoV2) in a permissive cells harboring cytotoxicity marker. The high-throughput compatible SARS-CoV-2 permissive reporter system that encompasses cells stably expressing hACE2 tagged cerulean and nuclear H2B tagged with mCherry, as a marker of nuclear condensation that also enabled imaging of fused cells among infected EGFP positive cells and could give real-time information of syncytia formation. Results: A limited high-throughput screening identified six natural products with marked VSV-eGFP-SARS-CoV2 inhibition at non cytotoxic dose. Molecular simulation studies with positive hits in complex with wild-type spike reaffirm their potential to impede viral entry. Real-time syncytia formation assay of the molecules revealed inhibition of syncytia with Didemnin B, and delayed inhibition with other natural products such as Scillaren A, Proscillaridin, Acetoxycycloheximide indicating that the assay is a reliable platform for any image based drug screening. Conclusion: BSL-2 compatible assay system equivalent to the infectious SARS-CoV-2 is a promising tool for high-throughput screening of large compound libraries for viral entry inhibitors against SARS-CoV-2 along with toxicity and effect on syncytia. Studies using clinical isolates of SARS-CoV-2 is warranted to confirm the antiviral potency of the leads and the utility of the screening system.

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“…Streptonigrin tetracyclic aminoquinoline-5,8 dione is an antitumor antibiotic, and previous screening against SARS-CoV-2 nsp15 endoribonuclease identified it as a positive hit [ 24 ]. Scillaren A is a cardiac glycoside derived from Drimia species [ 25 ] and in silico studies have been reported to have SARS-CoV-2 Mpro binding affinities [ 26 ]. In our present study, Scillaren A inhibits pseudovirion infection and Spike S1 binding.…”

Section: Discussionmentioning

confidence: 99%

A high-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity

et al. 2023

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Background The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is mediated through the binding of the SARS-CoV-2 Spike protein via the receptor binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2). Identifying compounds that inhibit Spike-ACE2 binding would be a promising and safe antiviral approach against COVID-19. Methods In this study, we used a BSL-2 compatible replication-competent vesicular stomatitis virus (VSV) expressing Spike protein of SARS-CoV-2 with eGFP reporter system (VSV-eGFP-SARS-CoV-2) in a recombinant permissive cell system for high-throughput screening of viral entry blockers. The SARS-CoV-2 permissive reporter system encompasses cells that stably express hACE2-tagged cerulean and H2B tagged with mCherry, as a marker of nuclear condensation, which also enables imaging of fused cells among infected EGFP positive cells and could provide real-time information on syncytia formation. Results A limited high-throughput screening identified six natural products that markedly inhibited VSV-eGFP-SARS-CoV-2 with minimum toxicity. Further studies of Spike-S1 binding using the permissive cells showed Scillaren A and 17-Aminodemethoxygeldanamycin could inhibit S1 binding to ACE2 among the six leads. A real-time imaging revealed delayed inhibition of syncytia by Scillaren A, Proscillaridin, Acetoxycycloheximide and complete inhibition by Didemnin B indicating that the assay is a reliable platform for any image-based drug screening. Conclusion A BSL-2 compatible assay system that is equivalent to the infectious SARS-CoV-2 is a promising tool for high-throughput screening of large compound libraries for viral entry inhibitors against SARS-CoV-2 along with toxicity and effects on syncytia. Studies using clinical isolates of SARS-CoV-2 are warranted to confirm the antiviral potency of the leads and the utility of the screening system.

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Searching and designing potential inhibitors for SARS-CoV-2 Mpro from natural sources using atomistic and deep-learning calculations

Abstract: The hybrid DeepFrag/atomistic simulation approach could lead to a new scheme for developing SARS-CoV-2 3CLpro/Mpro inhibitors.

Cited by 11 publications

References 76 publications

Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

A High-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity

A high-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity

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