Computational Biology and Bioinformatics

Submit a Manuscript

Publishing with us to make your research visible to the widest possible audience.

Propose a Special Issue

Building a community of authors and readers to discuss the latest research and develop new ideas.

Computational Studies and Scaffold Search for APOE4 as Coronary Artery Disease Target by Virtual Screening

Apolipoprotein E (APOE) polymorphism is involved in the pathogenesis of atherosclerosis and conveys a higher risk of coronary artery disease (CAD). The structural features of the isoforms (APOE2, APOE3, and APOE4) differ by only single amino acid that explicate their unique functions as lipid transporter with a role in cholesterol metabolism. It is therefore hypothesized that the cysteine/arginine change at position 112 results in structural differences within APOE3 and APOE4 leading to variation in binding affinities of ligands. We report for the first time computational and structural studies that reveal selectivity amongst ligands for APOE binding, with possible links to CAD pathogenesis. Molecular dynamics study allowed to understand the APOE conformational flexibility and its stability followed by Molecular docking studies that identified scaffold of Ligand 11802 by screening of 22,203 molecules from ChemDiv Library which showed the highest affinity towards APOE4. The ligand showed the presence of chemical moieties, similar to that present in known APOE4 stabilizers in Alzheimer’s Disease, which opened a possibility for the ligand as a potential therapeutic agent that could affect the behaviour of APOE4 in CAD pathogenesis. Further, ligand-binding preferences of each isoform with LDL receptors (LDLR) allowed understanding of the in-vivo mechanism in CAD pathogenesis.

Cardiovascular, Apolipoprotein, Molecular Docking, SAR, Atherosclerosis

Lima Hazarika, Supriyo Sen, Jitesh Doshi. (2022). Computational Studies and Scaffold Search for APOE4 as Coronary Artery Disease Target by Virtual Screening. Computational Biology and Bioinformatics, 10(2), 49-59.

Copyright © 2022 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Malakar AK, Choudhury D, Halder B, Paul P, Uddin A, Chakraborty S. A review on coronary artery disease, its risk factors, and therapeutics. Vol. 234, Journal of Cellular Physiology. Wiley-Liss Inc.; 2019. p. 16812–23. Available from:
2. Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A. Epidemiology of coronary heart disease and acute coronary syndrome. Vol. 4, Annals of Translational Medicine. AME Publishing Company; 2016. Available from: /pmc/articles/PMC4958723.
3. Hou J, Hou J, Hou J, Deng Q, Deng Q, Deng Q, et al. Association between apolipoprotein e gene polymorphism and the risk of coronary artery disease in Hakka postmenopausal women in southern China. Lipids Health Dis. 2020; 19 (1): 139. Available from:
4. Sing CF, Davignon J. Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. Am J Hum Genet. 1985; 37 (2): 268–85. Available from: /pmc/articles/PMC1684560.
5. Frieden C, Garai K. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proc Natl Acad Sci U S A. 2012; 109 (23): 8913–8. Available from: /pmc/articles/PMC3384159
6. Petros AM, Korepanova A, Jakob CG, Qiu W, Panchal SC, Wang J, et al. Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer. J Med Chem. 2019; 62: 4120–30.
7. Weisgraber KH. Apolipoprotein E: Structure-function relationships. Adv Protein Chem. 1994; 45: 249–302.
8. Lamia LF, Sharif FA, Abed AA. Relationship between ApoE gene polymorphism and coronary heart disease in Gaza Strip. J Cardiovasc Dis Res. 2011; 2 (1): 29–35. Available from:
9. Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med. 2016; 94 (7): 739–46. Available from:
10. Boulenouar H, Benchekor SM, Meroufel DN, Hetraf SAL, Djellouli HO, Hermant X, et al. Impact of APOE gene polymorphisms on the lipid profile in an Algerian population. Lipids Health Dis. 2013; 12 (1). Available from:
11. Huang HJ, Chen HY, Lee CC, Chen CYC. Computational design of apolipoprotein e4 inhibitors for Alzheimer’s disease therapy from traditional Chinese medicine. Biomed Res Int. 2014; 2014. 452625. doi: 10.1155/2014/452625.
12. Narayanaswami V, Ryan RO. Molecular basis of exchangeable apolipoprotein function. Vol. 1483, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2000. p. 15–36. doi: 10.1016/s1388-1981(99)00176-6.
13. Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: A HuGE review. Vol. 155, American Journal of Epidemiology. Oxford Academic; 2002. p. 487–95. Available from:
14. El-Lebedy D, Raslan HM, Mohammed AM. Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2016; 15 (1): 12. Available from:
15. Chen W, Jin F, Cao G, Mei R, Wang Y, Long P, et al. ApoE4 May be a Promising Target for Treatment of Coronary Heart Disease and Alzheimer’s Disease. Curr Drug Targets. 2018; 19 (9): 1038–44. Available from:
16. Liu S, Liu J, Weng R, Gu X, Zhong Z. Apolipoprotein e gene polymorphism and the risk of cardiovascular disease and type 2 diabetes. BMC Cardiovasc Disord. 2019; 19 (1): 213. Available from:
17. Mahley RW, Rall SC. Apolipoprotein E: Far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000; 1 (2000): 507–37. Available from:
18. Frieden C, Wang H, Ho CMW. A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions. Proc Natl Acad Sci U S A. 2017; 114 (24): 6292–7.
19. Luo J, Maréchal JD, Wärmländer S, Gräslund A, Perálvarez-Marín A. In silico analysis of the apolipoprotein E and the amyloid β peptide interaction: Misfolding induced by frustration of the salt bridge network. PLoS Comput Biol. 2010; 6 (2).
20. Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res. 2009 Apr; 50 Suppl (Suppl). Available from:
21. Goyal M, Grover S, Dhanjal JK, Goyal S, Tyagi C, Chacko S, et al. Novel Natural Structure Corrector of ApoE4 for Checking Alzheimer’s Disease: Benefits from High Throughput Screening and Molecular Dynamics Simulations. Biomed Res Int. 2013; 2013. Available from: /pmc/articles/PMC3845489/.
22. Williams B, Convertino M, Das J, Dokholyan N V. ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations. PLoS Comput Biol. 2015; 11 (10). Available from: /pmc/articles/PMC4623519/
23. Hazarika L, Sen S, Zawar A, Doshi J. Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies. J Drug Des Med Chem. 2021; 7 (2): 27–38. Available from:
24. Castrignanò T, De Meo PDO, Cozzetto D, Talamo IG, Tramontano A. The PMDB Protein Model Database. Nucleic Acids Res. 2006; 34: D306–D309. doi: 10.1093/nar/gkj105.
25. Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput Phys Commun. 1995; 91 (1–3): 43–56.
26. Forlilab/Meeko. GitHub - forlilab/Meeko: Interfacing RDKit and AutoDock. 2022. Available from:
27. Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. 2021; 61 (8): 3891–8. Available from:
28. Software RdkO-SC. RDKit. 2022. Available from:
29. Kozakov D, Hall DR, Xia B, Porter KA, Padhorny D, Yueh C, et al. The ClusPro web server for protein-protein docking. Nat Protoc. 2017; 12 (2): 255–78. doi: 10.1038/nprot.2016.169.
30. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011; 108 (36): 14813–8. Available from:
31. Chen B, Sun Y, Niu J, Jarugumilli GK, Wu X. Protein lipidation in cell signaling and diseases: function, regulation and therapeutic opportunities. Cell Chem Biol. 2018; 25 (7): 817. Available from: /pmc/articles/PMC6054547.
32. Nguyen D, Dhanasekaran P, Nickel M, Mizuguchi C, Watanabe M, Saito H, et al. Influence of Domain Stability on the Properties ofHuman Apolipoprotein E3 and E4 and Mouse Apolipoprotein E. Biochemistry. 2014; 53 (24): 4025. Available from: /pmc/articles/PMC4071092/.