In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents

Abstract

Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔGbinding towards SIRT2 protein than the native ligand (SirReal2) with values of − 59.9, − 57.4, − 53.5, and − 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.

Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

“…Herein, oxadiazole, benzoxazole, and indole-like scaffolds were reported in relation to SIRT2 inhibition [5,64], giving useful features to further screening novel chemotypes acting as SIRT2 inhibitors. By combining the structural information suggested by the assayed ChemDiv compounds with those already featured by the collected co-crystallized SIRT2 inhibitors, we were able to proceed with in silico screening and subsequent biochemical assays of a small library of in-house pyrazolo-pyrimidine derivatives [1][2][3][4][5]. As a consequence, the applied VS strategy could represent a useful approach to set up the identification of novel chemo-types targeting further proteins such as phosphodiesterase or enzymes, whose structure has been widely defined in the literature.…”

“…HDACs are enzymes that catalyze the removal of acetyl groups from acetylated lysine residues of (non)histone proteins to counteract the histone acetyltransferase (HATs) action. Recent studies have proven that sirtuins not only deacetylate substrates but also catalyze different post-translational modulations involving demyristoylation and desuccinylation [1][2][3][4].…”

Avances en modelos in silico para el descubrimiento rápido de fármacos: transformando la farmacología computacional

“…En otra investigación realizada por Ibrahim et al (2023), donde exploraron la capacidad de inhibidores de SIRT2 derivados de fuentes naturales como agentes anticancerígenos ISSN: 2773-7330 Vol. 6 No.…”

Identification of potential human pancreatic α-amylase inhibitors from natural products by molecular docking, MM/GBSA calculations, MD simulations, and ADMET analysis

“…The MM/GBSA is a vital approach for determining the binding energy of the complex because of its balance in speed and accuracy. The energy for binding of the ligand (L) to the receptor (R) to form the complex (RL) is ΔG bind = G R − G L − G RL [24][25][26].…”