Discovery of RdRp Thumb-1 as a novel broad-spectrum antiviral family of targets and MDL-001 as a potent broad-spectrum inhibitor thereof – Part I: A Bioinformatics and Deep Learning Approach

Publication date: Apr 02, 2024

Positive sense, single-stranded RNA (+ssRNA) viruses consist of 12+ viral families that contain mild pathogens to pandemic-causing viruses like SARS-CoV-2, yet all share a vital and highly conserved RNA-dependent RNA polymerase (RdRp). While RdRp is the target of several viral inhibitors, the active site has several pitfalls when translating in vitro inhibitors to the clinic. The highly polar residues within the active site often necessitate the use of highly polar or charged compounds, especially when designing nucleoside analog inhibitors, posing significant challenges in optimizing drug-likeness and membrane permeability for clinical efficacy. Here, we investigated the broad-spectrum potential of the allosteric Thumb-1 cryptic site of the RdRp, which to date has only been adequately studied in Hepatitis C Virus (HCV). To explore this potential antiviral target, we used a suite of bioinformatics techniques, including homology modeling and multiple sequence alignments, to reveal the conserved landscape of the Thumb-1 site across +ssRNA viruses. We then used ChemPrint, our Mol-GDL (Molecular-Geometric Deep Learning) machine learning model to predict drug inhibition of the Thumb-1 site in RdRp across +ssRNA viruses. Here, we identify MDL-001 as a promising broad-spectrum antiviral candidate with favorable properties that enable oral and once-a-day dosing. We also show how the cryptic nature of the Thumb-1 site masks itself to conventional virtual screening techniques, like docking, where activity prediction is heavily based on solving or predicting an accurate structure of the open pocket. This study demonstrates the utility of this approach in drug discovery for broad-spectrum antivirals that target the Thumb-1 site.

Concepts Keywords
Coxsackievirus Biorxiv
Expert Broad
Panda Chemprint
Phenylbenzimidazole Cov


Type Source Name
disease VO Viruses
pathway KEGG RNA polymerase
disease IDO site
drug DRUGBANK Gluconolactone
disease MESH Hepatitis
disease VO effective
disease IDO replication
drug DRUGBANK Phosphate ion
disease MESH COVID 19
pathway REACTOME Metabolism
drug DRUGBANK Beclabuvir
drug DRUGBANK Dasabuvir
drug DRUGBANK Sofosbuvir
drug DRUGBANK L-Leucine
drug DRUGBANK Amino acids
disease VO Coxsackievirus
drug DRUGBANK L-Phenylalanine
drug DRUGBANK L-Asparagine
drug DRUGBANK L-Tryptophan
drug DRUGBANK Proline
disease MESH Japanese Encephalitis
drug DRUGBANK Pentaerythritol tetranitrate
disease IDO assay
disease MESH infection
disease IDO process
drug DRUGBANK Saquinavir
drug DRUGBANK Indole
disease MESH Influenza
disease MESH infectious diseases
drug DRUGBANK Ritonavir
disease MESH viral diseases
disease IDO algorithm
disease IDO quality
drug DRUGBANK Water
disease VO Dengue virus
drug DRUGBANK Acetamide
drug DRUGBANK Acetazolamide
disease VO effectiveness

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