Computational design and validation of small molecule inhibitors for type III phosphatidylinositol-4-kinase alpha, a hepatitis C drug target.

Abstract

According to World Health Organization reports of the year 2022, nearly 242,000 people died from hepatitis C that causes liver cirrhosis and hepatocellular carcinoma. Phosphatidylinositol-4-kinase type III alpha (PI4KIIIα), a lipid kinase interacts with the hepatitis C virus non-structural 5 A protein (NS5A) to produce phosphoinositol-4-phosphate (PI4P), which enriches the hepatitis C virus replication complex. Patients with hepatitis C virus infection in the liver have been associated with increased levels of PI4P at the endoplasmic reticulum. To initiate viral replication, the hepatitis C virus must assemble numerous host cellular proteins into distinct membrane replication structures. A crucial element of these replication organelles is PI4KIIIα. Therefore, inhibition of PI4KIIIα is one of the most needed therapeutic approaches for the treatment of the disease. In this direction, a combination of pharmacophore-based virtual screening, molecular docking, molecular dynamics (MD) simulations were studied for PI4KIIIα. The stability of the complexes throughout MD simulations was evaluated from their binding free energies, post-MD analysis, and further the drug-like properties of the selected molecules were analyzed. Six molecules were finally selected as the likely hit molecules based on binding free energies, normal mode analysis, and their drug-like properties. The findings of this work suggest that the selected small molecules may be used as lead molecules for the development of novel PI4KIIIα inhibitors. It is also anticipated that these thorough studies will be helpful in the structure-based drug design of PI4KIIIα inhibitors.