Halogenated Baicalein as a Promising Antiviral Agent toward SARS-CoV-2 Main Protease

Abstract

The coronavirus disease pandemic is a constant reminder that global citizens are in imminent danger of exposure to emerging infectious diseases. Therefore, developing a technique for inhibitor discovery is essential for effective drug design. Herein, we proposed fragment molecular orbital (FMO)-based virtual screening to predict the molecular binding energy of potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitors. The integration of quantum mechanical approaches and trajectory analysis from a microsecond molecular dynamics simulation was used to identify potential inhibitors. We identified brominated baicalein as a potent inhibitor of the SARS-CoV-2 main protease and confirmed its inhibitory activity in an in vitro assay. Brominated baicalein did not demonstrate significant toxicity in either in vitro or in vivo studies. The pair interaction energy from FMO-RIMP2/PCM and inhibitory constants based on the protease enzyme assay suggested that the brominated baicalein could be further developed into novel SARS-CoV-2 protease inhibitors.

Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies

“…Upon ligand binding in the enzyme active site, i.e., protomer A, the average SASAs of all simulated models diminished by ∼120 to 450 Å 2 . This event was in accordance with our previous MD reports on lopinavir/ritonavir [41] , peptidomimetic inhibitors (compound N3, 11a, 13b and 14b) [71] and halogenated baicalein [84] bound to SARS-CoV-2 M pro , which showed a significant reduction in SASAs during the binding process. Moreover, to compare the enantiomer system, it can be noticed that the ( S )- 3l system exhibited lower SASAs than the ( R )- 3l system, whereas the ( S )- 3t system showed higher SASAs than the ( R )- 3t system.…”

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases

“…For example, the previously reported −NH and N moieties of pyrazole in 4-amino-(1 H )-pyrazole compounds could form hydrogen bonds with the hinge region of JAK2, including E930 and L932, and pyrazolo-pyrimidine analogues with fluorine atoms showed potent JAK2 inhibition (27 nM) . A halogen-substituted compound has also been considered in drug discovery and design. − The pharmacological properties of these compounds were also predicted to verify whether these screened pyrazolone derivatives can be used as a good candidate for JAKs inhibitors. All the screened compounds obey Lipinski’s rule (Table S1), suggesting that they could be candidates for novel JAK2/3 inhibitors.…”

Hotspot Identification and Drug Design of Protein–Protein Interaction Modulators Using the Fragment Molecular Orbital Method

“…Many research groups have used FMO to identify interactions in protein–small molecule and protein–protein complexes. For example, the FMO protocol has been extensively used for exploration of interactions between the COVID-19 main protease and its inhibitors, , class A G protein-coupled receptors (GPCRs) and their ligands, in discovery of ITK (kinase) and of Hsp90 inhibitors and in many other SBDD programs . In recent years, the use of FMO has been expanded to the structural analysis of proteins, , e.g., in the investigation of interactions between transmembrane helices of GPCRs, , SARS-Cov-2-related proteins, , and several other PPI targets. ,,− …”