title: Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations.
abstract: A major genetic suspect for Alzheimer's disease is the pathological conformation assumed by apolipoprotein E4 (ApoE4) through intramolecular interaction. In the present study, a large library of natural compounds was screened against ApoE4 to identify novel therapeutic molecules that can prevent ApoE4 from being converted to its pathological conformation. We report two such natural compounds PHC and IAH that bound to the active site of ApoE4 during the docking process. The binding analysis suggested that they have a strong mechanistic ability to correct the pathological structural orientation of ApoE4 by preventing repulsion between Arg 61 and Arg 112, thus inhibiting the formation of a salt bridge between Arg 61 and Glu 255. However, when the molecular dynamics simulations were carried out, structural changes in the PHC-bound complex forced PHC to move out of the cavity thus destabilizing the complex. However, IAH was structurally stable inside the binding pocket throughout the simulations trajectory. Our simulations results indicate that the initial receptor-ligand interaction observed after docking could be limited due to the receptor rigid docking algorithm and that the conformations and interactions observed after simulation runs are more energetically favored and should be better representations of derivative poses in the receptor.
authors: Apaji Institute of Mathematics & Applied Computer Technology, Banasthali University, Tonk, Rajasthan 304022, India.
authors: Manisha
authors: M
authors: Goyal
authors: Sonam
authors: S
authors: Grover
authors: Jaspreet Kaur
authors: JK
authors: Dhanjal
authors: Sukriti
authors: S
authors: Goyal
authors: Chetna
authors: C
authors: Tyagi
authors: Sajeev
authors: S
authors: Chacko
authors: Abhinav
authors: A
authors: Grover
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D053327:Apolipoprotein E4 / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D057166:High-Throughput Screening Assays; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D017967:Zinc Compounds / Q000737:chemistry*
chemical_list: D053327:Apolipoprotein E4; D017967:Zinc Compounds