Discovery of Natural Bisbenzylisoquinoline Analogs from the Library of Thai Traditional Plants as SARS-CoV-2 3CLPro Inhibitors: In Silico Molecular Docking, Molecular Dynamics, and In Vitro Enzymatic Activity

• DOI: 10.1021/acs.jcim.2c01309
• Publication Date: 2023-01-17T07:43:44Z
• Authors: Nopawit Khamto; Kraikrit Utama; Suriya Tateing; Padchanee Sangthong; Puracheth Rithchu...; Nathaporn Cheechana; Aroonchai Saiai; Natthawat Semakul; Winita Punyodom; Puttinan Meepowpan
• Keywords: ADME; Molecular mechanics; Docking (animal)

The emergence of SARS-CoV-2 in December 2019 has become a global issue due to the continuous upsurge patients and lack drug efficacy for treatment. 3CLPro is one most intriguing biomolecular targets among scientists worldwide developing antiviral drugs its relevance viral replication transcription. Herein, we utilized computer-assisted screening investigate 326 natural products from Thai traditional plants using structure-based virtual against 3CLPro. Following screening, top 15 compounds based on binding energy their interactions with key amino acid Cys145 were obtained. Subsequently, they further evaluated protein–ligand complex stability via molecular dynamics simulation free calculation mechanics Poisson–Boltzmann surface area (MM-PBSA) approaches. drug-likeness ADME/Tox assessments, seven bisbenzylisoquinolines obtained, including neferine (3), liensinine (4), isoliensinine (5), dinklacorine (8), tiliacorinine (13), 2′-nortiliacorinine (14), yanangcorinine (15). These computationally showed higher affinity than native N3 GC-373 inhibitors attained stable active site 3CLpro during 100 ns (MD) simulation. Moreover, vitro enzymatic assay that could experimentally inhibit To our delight, (5) isolated Nelumbo nucifera demonstrated highest inhibition protease activity IC50 value 29.93 μM low toxicity Vero cells. Our findings suggested bisbenzylisoquinoline scaffolds be potentially used as an vivo model development effective anti-SARS-CoV-2 drugs.