Identification of novel scaffolds targeting SIRT3 through molecular modeling techniques for the treatment of Hepatocellular carcinoma

• Published in: Journal of biomolecular structure & dynamics Vol. 42; no. 19; pp. 10165 - 10174
• Main Authors: Maya Ramírez, Carlos Eliel, Shokat, Zeeshan, Sufyan, Muhammad, Rehman, Md Tabish, AlAjmi, Mohamed F., Rather, Gulam M.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.12.2024
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Carcinoma, Hepatocellular - drug therapy; Catalytic Domain; computer aided drug designing; cSIRT3; Hepatocellular carcinoma; Humans; Ligands; Liver Neoplasms - drug therapy; MD simulation; mMGBSA; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Sirtuin 3 - chemistry; Sirtuin 3 - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; MD simulation; Hepatocellular carcinoma; cSIRT3; computer aided drug designing; mMGBSA
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2023.2256402

Hepatocellular carcinoma is one of the top causes of cancer-related death globally. SIRT3 belongs to the Sirtuin family of proteins, a collection of NAD+-dependent enzymes that play a role in controlling several cellular functions, including metabolism, aging, and stress response. SIRT3 expression has been discovered to be often downregulated in HCC tissues relative to normal liver tissues. Hence, SIRT3 may function as a tumor suppressor in HCC. In the present study, pharmacophore-based virtual screening of a small molecule database was performed initially, and then the screened hits were docked to the active site of SIRT3 to choose the best binding modes. One co-crystal ligand (PDB name: 1NQ) was utilized as a template to generate pharmacophore model query. A total of 0.2 million compounds from the VITAS-M Lab database were downloaded and prepared for virtual screening. Following database preparation, ligand-based virtual screening was performed using the pharmacophore query model generated in the previous phase. The compounds with the same pharmacophoric characteristics as the query at the same distance were screened. There were a total of 74 hits that matched the query model. These compounds were then docked to the SIRT3 using the standard precision protocol of the glide tool. To select hits with high binding affinities, a threshold of −8 kcal/mol was used. Based on the glide gscore, two hits were chosen. These two hits were selected to investigate the stability of the protein-ligand complex by molecular dynamics simulation. All of these findings indicate that the selected hit compounds C1 and C2 can serve as lead compounds in inhibiting the biological activity of SIRT3 requiring further detailed investigations. Communicated by Ramaswamy H. Sarma