Modeling structure–activity relationships with machine learning to identify GSK3-targeted small molecules as potential COVID-19 therapeutics

Abstract

Coronaviruses induce severe upper respiratory tract infections, which can spread to the lungs. The nucleocapsid protein (N protein) plays an important role in genome replication, transcription, and virion assembly in SARS-CoV-2, the virus causing COVID-19, and in other coronaviruses. Glycogen synthase kinase 3 (GSK3) activation phosphorylates the viral N protein. To combat COVID-19 and future coronavirus outbreaks, interference with the dependence of N protein on GSK3 may be a viable strategy. Toward this end, this study aimed to construct robust machine learning models to identify GSK3 inhibitors from Food and Drug Administration–approved and investigational drug libraries using the quantitative structure–activity relationship approach. A non-redundant dataset consisting of 495 and 3070 compounds for GSK3α and GSK3β, respectively, was acquired from the ChEMBL database. Twelve sets of molecular descriptors were used to define these inhibitors, and machine learning algorithms were selected using the LazyPredict package. Histogram-based gradient boosting and light gradient boosting machine algorithms were used to develop predictive models that were evaluated based on the root mean square error and R-squared value. Finally, the top two drugs (selinexor and ruboxistaurin) were selected for molecular dynamics simulation based on the highest predicted activity (negative log of the half-maximal inhibitory concentration, pIC50 value) to further investigate the structural stability of the protein-ligand complexes. This artificial intelligence-based virtual high-throughput screening approach is an effective strategy for accelerating drug discovery and finding novel pharmacological targets while reducing the cost and time.

Classification, replication, and transcription of Nidovirales

“…GSK-3 has been proved to be essential for the phosphorylation of SARS-CoV-2 N protein and the synthesis of viral RNA, serving as a promising target for developing pharmaceuticals to treat COVID-19 ( Wu et al, 2014 ; Liu et al, 2021 ). A non-redundant dataset containing 495 compounds for GSK3α and 3,070 compounds for GSK3β has been applied to virtual high-throughput screening and two drugs (selinexor and ruboxistaurin) have been selected for further investigation ( Pirzada et al, 2023 ). Therefore, interference with the phosphorylation of N protein by targeting GSK-3 is a feasible strategy to combat against the coronavirus associated diseases.…”

Respiratory RNA viruses: Molecular mechanisms of viral replication and pathogenicity

“…GSK-3 has been proved to be essential for the phosphorylation of SARS-CoV-2 N protein and the synthesis of viral RNA, serving as a promising target for developing pharmaceuticals to treat COVID-19 (Wu et al, 2014;. A non-redundant dataset containing 495 compounds for GSK3α and 3,070 compounds for GSK3β has been applied to virtual high-throughput screening and two drugs (selinexor and ruboxistaurin) have been selected for further investigation (Pirzada et al, 2023). Therefore, interference with the phosphorylation of N protein by targeting GSK-3 is a feasible strategy to combat against the coronavirus associated diseases.…”