Pharmacokinetic, DFT Modeling, Molecular Docking, and Molecular Dynamics Simulation Approaches: Diptoindonesin A as a Potential Inhibitor of Sirtuin-1

Abstract

Sirtuin 1 (SIRT1) is a class III histone deacetylase that regulates several cellular processes. SIRT1 overexpression is found in many cancer cases and is a potential therapeutic target. Unlike resveratrol, several stilbenoid dimers have been identified as SIRT1 inhibitors. This work studied the interaction and dynamic behavior of stilbenoid dimers and SIRT1. Prediction of binding free energy (∆Gbind) was calculated using the QM/MM-GBSA approach for each system, which resulted in 1NS-SIRT1: -21.44 kcal/mol, DS1-SIRT1: -25.94 kcal/mol, and DS2-SIRT1: -12.48 kcal/mol. These indicated that DS1 has a better chance as a SIRT1 inhibitor than DS2. The presence of glucose groups in DS1 potentially increased intermolecular interactions in the form of key residues and hydrogen bonds. Additionally, the quantum mechanical properties of DS1 and DS2 using the DFT/B3LYP/6-311++G(d,p) method were applied. The DS1 has three hydroxyls in the glucose group (3'-OH, 4'-OH, and 6'-OH) that could be reactive as nucleophiles and electrophiles. Furthermore, pharmacokinetic studies showcased the non-toxic properties of DS1. The analyses presented in this study could provide information on the quantum mechanical properties and inhibitory efficiency of stilbenoid dimers based on computational studies.