Discovery of Natural Bisbenzylisoquinoline Analogs from the Library of Thai Traditional Plants as SARS-CoV-2 3CL Pro Inhibitors: In Silico Molecular Docking, Molecular Dynamics, and In Vitro Enzymatic Activity.
Nopawit KhamtoKraikrit UtamaSuriya TateingPadchanee SangthongPuracheth RithchumponNathaporn CheechanaAroonchai SaiaiNatthawat SemakulWinita PunyodomPuttinan MeepowpanPublished in: Journal of chemical information and modeling (2023)
The emergence of SARS-CoV-2 in December 2019 has become a global issue due to the continuous upsurge in patients and the lack of drug efficacy for treatment. SARS-CoV-2 3CL Pro is one of the most intriguing biomolecular targets among scientists worldwide for developing antiviral drugs due to its relevance in viral replication and transcription. Herein, we utilized computer-assisted drug screening to investigate 326 natural products from Thai traditional plants using structure-based virtual screening against SARS-CoV-2 3CL Pro . Following the virtual screening, the top 15 compounds based on binding energy and their interactions with key amino acid Cys145 were obtained. Subsequently, they were further evaluated for protein-ligand complex stability via molecular dynamics simulation and binding free energy calculation using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches. Following drug-likeness and ADME/Tox assessments, seven bisbenzylisoquinolines were obtained, including neferine ( 3 ), liensinine ( 4 ), isoliensinine ( 5 ), dinklacorine ( 8 ), tiliacorinine ( 13 ), 2'-nortiliacorinine ( 14 ), and yanangcorinine ( 15 ). These compounds computationally showed a higher binding affinity than native N3 and GC-373 inhibitors and attained stable interactions on the active site of 3CL pro during 100 ns in molecular dynamics (MD) simulation. Moreover, the in vitro enzymatic assay showed that most bisbenzylisoquinolines could experimentally inhibit SARS-CoV-2 3CL Pro . To our delight, isoliensinine ( 5 ) isolated from Nelumbo nucifera demonstrated the highest inhibition of protease activity with the IC 50 value of 29.93 μM with low toxicity on Vero cells. Our findings suggested that bisbenzylisoquinoline scaffolds could be potentially used as an in vivo model for the development of effective anti-SARS-CoV-2 drugs.
Keyphrases
- sars cov
- molecular docking
- molecular dynamics
- molecular dynamics simulations
- respiratory syndrome coronavirus
- density functional theory
- anti inflammatory
- amino acid
- end stage renal disease
- chronic kidney disease
- hydrogen peroxide
- high throughput
- ejection fraction
- drug induced
- prognostic factors
- newly diagnosed
- transcription factor
- small molecule
- patient reported outcomes
- tissue engineering
- endoplasmic reticulum stress
- patient reported
- pi k akt