Delineating binding potential, stability of Sulforaphane‐N‐acetyl‐cysteine in the active site of histone deacetylase 2 and testing its cytotoxicity against distinct cancer lines through stringent molecular dynamics, DFT and cell‐based assays. (19th June 2021)

• Record Type: Journal Article
• Authors: Ganai, Shabir Ahmad; Srinivasan, Pappu; Rajamanikandan, Sundaraj; Shah, Basit Amin; Mohan, Suma; Gani, Mudasir; Padder, Bilal Ahmad; Qadri, Raies A.; Bhat, M. A.; Baba, Zahoor Ahmad; Yatoo, Manzoor Ahmad
• Is Part Of: Chemical biology & drug design. Volume 98:Number 3(2021)
• Page Start: 363
• Page End: 376
• Publication Date: 2021-06-19
• Subjects: DFT -- E‐Pharmacophores method -- HDAC2 -- MM‐GBSA -- molecular docking -- molecular dynamics -- MTT assay -- mutation -- neurodegenerative disorders -- SFN‐NAC -- Sulforaphane; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13854
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: Histone deacetylase 2 (HDAC2), an isozyme of Class I HDACs has potent imputations in actuating neurodegenerative signaling. Currently, there are sizeable therapeutic disquiets with the use of synthetic histone deacetylase inhibitors in disease management. This strongly suggests the unfulfilled medical necessity of plant substitutes for therapeutic intervention. Sulforaphane‐N‐acetyl‐cysteine (SFN‐N‐acetylcysteine or SFN‐NAC), a sulforaphane metabolite has shown significantly worthier activity against HDACs under in vitro conditions. However, the atomistic studies of SFN‐NAC against HDAC2 are currently lacking. Thus, the present study employed a hybrid strategy including extra‐precision (XP) grid‐based flexible molecular docking, molecular mechanics generalized born surface area (MM‐GBSA), e‐Pharmacophores method, and molecular dynamics simulation for exploring the binding strengh, mode of interaction, e‐Pharmacophoric features, and stability of SFN‐NAC towards HDAC2. Further, the globally acknowledged density functional theory (DFT) study was performed on SFN‐NAC and entinostat individually in complex state with HDAC2. Apart from this, these inhibitors were tested against three distinct cancer cell models and one transformed cell line for cytotoxic activity. Moreover, double mutant of HDAC2 was generated and the binding orientation and interaction of SFN‐NAC was scrutinized in this state. On the whole, this study unbosomed and explained the comparatively higher binding affinity of entinostat for HDAC2 and its wide spectrum cytotoxicity than SFN‐NAC. Abstract : Blurb content: Binding potential and stability of synthetic HDAC inhibitor entinostat was compared with plant HDAC inhibitor Sulphoraphane N‐acetyl‐cysteine (sulphoraphane metabolite) against therapeutic target HDAC2. This was done using different techniques such as high precision molecular docking, binding free energy estimation and molecular dynamics simulation. The stability was further validated by futuristic technique DFT. These inhibitors were tested for cytotoxic effect against three distinct cancer cell lines including human breast cancer cell line (epithelial), lung adenocarcinoma, rat glioma and transformed cell line HEK‐293T.