Key result
Screening of 700 antivirals identifies Sorafenib, YM201636, and LDC4297 as compelling norovirus 3CL protease inhibitors.
Why the study?
Human norovirus causes substantial global morbidity and death, but there are presently no authorized vaccines, small-molecule therapies, or prophylactics.
Effect estimate: BE -11.67, -10.34, and -9.78 kcal/mol
Computational screening identified Sorafenib, YM201636, and LDC4297 as potential inhibitors of human norovirus 3CL protease, requiring future in vitro validation.
These hits merit in vitro validation as norovirus antivirals; hypothesis-generating and leaves open any clinical role.
Human noroviruses (NV) are the most prevalent cause of sporadic and pandemic acute gastroenteritis. NV infections cause substantial morbidity and death globally, especially amongst the aged, immunocompromised individuals, and children. There are presently no authorized NV vaccines, small-molecule therapies, or prophylactics for humans. NV 3 C L protease (3CLP) has been identified as a promising therapeutic target for anti-NV drug development. Herein, we employed a structure-based virtual screening method to screen a library of 700 antiviral compounds against the active site residues of 3CLP. We report three compounds, Sorafenib, YM201636, and LDC4297, that were revealed to have a higher binding energy (BE) value with 3CLP than the control (Dipeptidyl inhibitor 7) following a sequential screening, in-depth molecular docking and visualization, physicochemical and pharmacological property analysis, and molecular dynamics (MD) study. Sorafenib, YM201636, and LDC4297 had BEs of -11.67, -10.34, and -9.78 kcal/mol with 3CLP, respectively, while control had a BE of -6.38 kcal/mol. Furthermore, MD simulations of the two best compounds and control were used to further optimize the interactions, and a 100 ns MD simulation revealed that they form stable complexes with 3CLP. The estimated physicochemical, drug-like, and ADMET properties of these hits suggest that they might be employed as 3CLP inhibitors in the management of gastroenteritis. However, wet lab tests are a prerequisite to optimize them as NV 3CLP inhibitors.
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He et al. (2022) studied Human norovirus gastroenteritis (in silico target). Sorafenib, YM201636, and LDC4297 vs. Dipeptidyl inhibitor 7 was evaluated on Binding energy (BE) with 3CLP (BE -11.67, -10.34, and -9.78 kcal/mol). In silico screening identified Sorafenib, YM201636, and LDC4297 as compelling inhibitors of human norovirus 3CL protease with binding energies of -11.67, -10.34, and -9.78 kcal/mol, respectively.
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