Molecular dynamics and quantum chemistry-based approaches to identify isoform selective HDAC2 inhibitor - a novel target to prevent Alzheimer's disease

摘要

Histone deacetylase 2 (HDAC2) is an emerging target of Alzheimer's disease. Four featured pharmacophore model (ADRR) with one H-bond acceptor (A), one H-bond donor (D), and two aromatic rings (R) was generated using experimentally reported compounds, ((E-5[3-benzenesulfonamido) phenyl]-N-hydroxypent-2-en-4-ynamide)) and (N'-hydroxy-N-phenyloctanediamide) with IC50 values of 0.16 +/- 0.11 nM and 62 +/- 0.15 nM, respectively. Quantum Polarized Ligand Docking and Binding Free Energy calculation was performed for the top three identified leads RH01652, JFD02573, and HTS00800 from HitFinder database. RH01652 (methyl 2-[({5-[(benzoylamino) methyl]-2-thienyl} sulfonyl) amino]-3-(1H-indo1-3-yl) propanoate) with docking score (-12.62 kcal/mol) and binding free energy (-75.27 kcal/ mol), shows good binding affinity. RH01652 interacts with Gly154, His183, Glu208, and Phe210 with four H-bonds and stabilized by pi-pi interactions with His146, Tyr209, and Phe210. DFT studies at B3LYP level with 6-31G* basis set for the lead RH01652 reveals low band gap/AE (E-HOMO E-LUMO) of -0.16eV, which illustrates good reactivity of the lead. MD simulation studies (40ns) was performed to confirm the stability of lead binding. Comparative molecular docking studies of the lead RH01652 with class I HDACs (HDAC1, HDAC2, HDAC3, and HDAC8) shows higher binding affinity towards HDAC2. Thus, lead RH01652 could serve as template to design novel and potent inhibitor of HDAC2.