Integrating pharmacophore mapping, virtual screening, density functional theory, molecular simulation towards the discovery of novel apolipoprotein (apoE ε4) inhibitors

AIM An integrated protocol of virtual screening involving molecular docking, pharmacophore probing, and simulations was established to identify small novel molecules targeting crucial residues involved in the variant apoE ε4 to mimic its behavior as apoE2 thereby eliminating the amyloid plaque accumulation and facilitating its clearance. MATERIALS AND METHODS An excellent ligand-based and structure-based approach was made to identify common pharmacophoric features involving structure-based docking with respect to apoE ε4 leading to the development of apoE ε4 inhibitors possessing new scaffolds. An effort was made to design multiple-substituted triazine derivatives series bearing a novel scaffold. A structure-based pharmacophore mapping was developed to explore the binding sites of apoE ε4 which was taken into consideration. Subsequently, virtual screening, ADMET, DFT searches were at work to narrow down the proposed hits to be forwarded as a potential drug likes candidates. Further, the binding patterns of the best-proposed hits were studied and were forwarded for molecular dynamic simulations of 10 ns for its structural optimization. RESULTS Selectivity profile for the most promising candidates was studied, revealing significantly C13 and C15 to be the most potent compounds. The proposed hits can be forwarded for further study against apoE ε4 involved in neurological disorder Alzheimer's.

[1]  D. Sriram,et al.  Discovery of novel inhibitors of Mycobacterium tuberculosis MurG: homology modelling, structure based pharmacophore, molecular docking, and molecular dynamics simulations , 2018, Journal of biomolecular structure & dynamics.

[2]  Sugunadevi Sakkiah,et al.  Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors , 2012, Acta Pharmacologica Sinica.

[3]  David Calkins,et al.  Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution , 2010, J. Comput. Aided Mol. Des..

[4]  M. Coumar,et al.  BDMC-A, an analog of curcumin, inhibits markers of invasion, angiogenesis, and metastasis in breast cancer cells via NF-κB pathway--A comparative study with curcumin. , 2015, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[5]  S. Singh,et al.  Identification of selective MMP-9 inhibitors through multiple e-pharmacophore, ligand-based pharmacophore, molecular docking, and density functional theory approaches , 2019, Journal of biomolecular structure & dynamics.

[6]  Rebecca F. Halperin,et al.  A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. , 2007, The Journal of clinical psychiatry.

[7]  Kwang Kim,et al.  Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors , 2011, BMC Bioinformatics.

[8]  V. Pande,et al.  Activation pathway of Src kinase reveals intermediate states as novel targets for drug design , 2014, Nature Communications.

[9]  M. Sengupta,et al.  Altered Levels of Amyloid Precursor Protein Intracellular Domain-interacting Proteins in Alzheimer Disease , 2014, Alzheimer disease and associated disorders.

[10]  Asim Kumar Debnath,et al.  Pharmacophore mapping of a series of 2,4-diamino-5-deazapteridine inhibitors of Mycobacterium avium complex dihydrofolate reductase. , 2002, Journal of medicinal chemistry.

[11]  M. Dimachkie,et al.  Donepezil in the treatment of Alzheimer disease. , 2000 .

[12]  Charles L. Brooks,et al.  Detailed analysis of grid‐based molecular docking: A case study of CDOCKER—A CHARMm‐based MD docking algorithm , 2003, J. Comput. Chem..

[13]  Weiliang Zhu,et al.  Nonbonding interactions of organic halogens in biological systems: implications for drug discovery and biomolecular design. , 2010, Physical chemistry chemical physics : PCCP.

[14]  Zaheer-ul-Haq,et al.  Juliflorine: a potent natural peripheral anionic-site-binding inhibitor of acetylcholinesterase with calcium-channel blocking potential, a leading candidate for Alzheimer's disease therapy. , 2005, Biochemical and biophysical research communications.

[15]  J. Haines,et al.  Genome-Wide Association Study of Late-Onset Alzheimer Disease Identifies Disease-Associated Variants in MS4A4/MS4A6E, CD2AP, CD33, and EPHA1 , 2011, Alzheimer's & Dementia.

[16]  R. Nussbaum Genome-wide association studies, Alzheimer disease, and understudied populations. , 2013, JAMA.

[17]  E. Tadaka,et al.  Effects of reminiscence group in elderly people with Alzheimer disease and vascular dementia in a community setting , 2007 .

[18]  Aftab Ahmad,et al.  Synthesis, molecular docking with COX 1& II enzyme, ADMET screening and in vivo anti-inflammatory activity of oxadiazole, thiadiazole and triazole analogs of felbinac , 2017 .

[19]  Arthur J. Olson,et al.  Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein–ligand binding challenge , 2014, Journal of Computer-Aided Molecular Design.

[20]  Kai Gu,et al.  Therapeutic Agents in Alzheimer's Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core. , 2017, Current topics in medicinal chemistry.

[21]  Diganta Sarma,et al.  Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[22]  Keun Woo Lee,et al.  Pharmacophore modeling, virtual screening, molecular docking studies and density functional theory approaches to identify novel ketohexokinase (KHK) inhibitors , 2015, Biosyst..