Application of an R-group Search Strategy into Three-dimensional Quantitative Structure-activity Relationship of HEA β-secretase Inhibitors and Molecular Virtual Screening_Journal of Biomedical Engineering

Authors：

SHIBozhi , LIUYonglan , LIYueting , WANGGuixue ,  LIANGGuizhao

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China;

Corresponding author：

LIANGGuizhao, Email: gzliang@cqu.edu.cn

Keywords：

β-secretase; three-dimensional quantitative structure-activity relationship; R-groups; Topomer CoMFA; Topomer Search; molecular docking

DOI：

10.7507/1001-5515.20140038

Video：

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The β-secretase is one of prospective targets against Alzheimer's disease (AD). A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of Hydroethylamines (HEAs) as β-secretase inhibitors was established using Topomer CoMFA. The multiple correlation coefficient of fitting, cross validation and external validation were r²=0.928, q_loo²=0.605 and r_pred²=0.626, respectively. The 3D-QSAR model was used to search R groups from ZINC database as the source of structural fragments. As a result, a series of R groups with relatively high activity contribution was obtained to design a total of 15 new compounds, with higher activity than that of the template molecule. The molecular docking was employed to study the interaction mode between the new compounds as ligands and β-secretase as receptors, displaying that hydrogen bond and hydrophobicity played important roles in the binding affinity between the new compounds and β-secretase. The results showed that Topomer CoMFA and Topomer Search could be effectively used to screen and design new molecules of HEAs as β-secretase inhibitors, and the designed compounds could provide new candidates for drug design targeting AD.

Citation： SHIBozhi, LIUYonglan, LIYueting, WANGGuixue, LIANGGuizhao. Application of an R-group Search Strategy into Three-dimensional Quantitative Structure-activity Relationship of HEA β-secretase Inhibitors and Molecular Virtual Screening. Journal of Biomedical Engineering, 2014, 31(1): 196-204. doi: 10.7507/1001-5515.20140038 Copy

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6.	GHOSH A K, BRINDISI M, TANG J. Developing β-secretase inhibitors for treatment of Alzheimer's disease[J]. J Neurochem, 2012, 120(Suppl 1):71-83.
7.	OHNO M, SAMETSKY E A, YOUNKIN L H, et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease[J]. Neuron, 2004, 41(1):27-33.
8.	DE STROOPER B. Proteases and proteolysis in Alzheimer disease:a multifactorial view on the disease process[J]. Physiol Rev, 2010, 90(2):465-494.
9.	YAN R Q, MUNZNER J B, SHUCK M E, et al. BACE2 functions as an alternative α-secretase in cells[J]. J Biol Chem, 2001, 276(36):34019-34027.
10.	ATWAL J K, CHEN Y, CHIU C, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo[J]. Sci Trans Med, 2011, 3(84):84ra43.
11.	JENKINS C L, BRETSCHER L E, GUZEI I A, et al. Effect of 3-hydroxyproline residues on collagen stability[J]. J Am Chem Soc, 2003, 125(21):6422-6427.
12.	HOM R K, GAILUNAS A F, MAMO S, et al. Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human β-secretase[J]. J Med Chem, 2003, 47(1):158-164.
13.	MAILLARD M C, HOM R K, BENSON T E, et al. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase[J]. J Med Chem, 2007, 50(4):776-781.
14.	RAJAPAKSE H A, NANTERMET P G, SELNICK H G, et al. Discovery of oxadiazoyl tertiaiy carbinamine inhibitors of β-secretase (BALE-1)[J]. J Med Chem, 2006, 49(25):7270-7273.
15.	FRESKOS J N, FOBIAN Y M, BENSON T E, et al. Design of potent inhibitors of human beta-secretase. Part 1[J]. Bioorg Med Chem Lett, 2007, 17(1):73-77.
16.	HUSSAIN I, HAWKINS J, HARRISON D, et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo[J]. J Neurochem, 2007, 100(3):802-809.
17.	CLARKE B, DEMONT E, DINGWALL C, et al. BACE-1 inhibitors part 1:identification of novel hydroxy ethylamines (HEAs)[J]. Bioor Med Chem Lett, 2008, 18(3):1011-1016.
18.	CHARRIER N, CLARKE B, CUTLER L, et al. Second generation of hydroxyethylamine BACE-1 inhibitors:optimizing potency and oral bioavailability[J]. J Med Chem, 2008, 51(11):3313-3317.
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25.	KUNTZ I D, BLANEY J M, OATLEY S J, et al. A geometric approach to macromolecule-ligand interactions[J]. J Mol Biol, 1982, 161(2):269-288.
26.	ELDRIDGE M D, MURRAY C W, AUTON T R, et al. Empirical scoring functions:Ⅰ. the development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes[J]. J Comput Aided Mol Des, 1997, 11(5):425-445.
27.	MUEGGE I, MARTIN Y C. A general and fast scoring function for protein-ligand interactions:a simplified potential approach[J]. J Med Chem, 1999, 42(5):791-804.
28.	CRAMER R D, PATTERSON D E, BUNCE J D. Comparative molecular field analysis (CoMFA). 1. effect of shape on binding of steroids to carrier proteins[J]. J Am Chem Soc, 1988, 110(18):5959-5967.
29.	JILEK R J, CRAMER R D. Topomers:a validated protocol for their self-consistent generation[J]. J Chem Inf Comput Sci, 2004, 44(4):1221-1227.
30.	CRAMER R D, JILEK R J, ANDREWS K M. Dbtop:topomer similarity searching of conventional structure databases[J]. J Mol Graph Model, 2002, 20(6):447-462.
31.	JAIN A N. Scoring noncovalent protein-ligand interactions:a continuous differentiable function tuned to compute binding affinities[J]. J Comput Aided Mol Des. 1996, 10(5):427-440.
32.	CLARK R D, STRIZHEV A, LEONARD J M, et al. Consensus scoring for ligand/protein interactions[J]. J Mol Graph Model, 2002, 20(4):281-295.
33.	CHARIFSON P S, CORKERY J J, MURCKO M A, et al. Consensus scoring:a method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins[J]. J Med Chem, 1999, 42(25):5100-5109.
34.	MANOHARAN P, VIJAYAN R S, GHOSHAL N. Rationalizing fragment based drug discovery for BACE1:insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies[J]. J Comput Aided Mol Des, 2010, 24(10):843-864.

1. BLENNOW K, DE LEON M J, ZETTERBERG H. Alzheimer's disease[J]. Lancet, 2006, 368(9533):387-403.
2. BULIC B, PICKHARDT M, KHLISTUNOVA I, et al. Rhodanine-based Tau aggregation inhibitors in cell models of tauopathy[J]. Angew Chem Int Ed Engl, 2007, 46(48):9215-9219.
3. WOLFE M S. Secretase target for Alzhermer's disease:identification and therapeutic potential[J]. J Med Chem, 2001, 44(13):2039-2060.
4. HONG L, KOELSCH G, LIN X, et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor[J]. Science, 2000, 290(5489):150-153.
5. GHOSH A K, BILCER G, HARWOOD C, et al. Structure based design:potent inhibitors of human brain mernapsin 2 (β-secretase)[J]. J Med Chem, 2001, 44(18):2865-2868.
6. GHOSH A K, BRINDISI M, TANG J. Developing β-secretase inhibitors for treatment of Alzheimer's disease[J]. J Neurochem, 2012, 120(Suppl 1):71-83.
7. OHNO M, SAMETSKY E A, YOUNKIN L H, et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease[J]. Neuron, 2004, 41(1):27-33.
8. DE STROOPER B. Proteases and proteolysis in Alzheimer disease:a multifactorial view on the disease process[J]. Physiol Rev, 2010, 90(2):465-494.
9. YAN R Q, MUNZNER J B, SHUCK M E, et al. BACE2 functions as an alternative α-secretase in cells[J]. J Biol Chem, 2001, 276(36):34019-34027.
10. ATWAL J K, CHEN Y, CHIU C, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo[J]. Sci Trans Med, 2011, 3(84):84ra43.
11. JENKINS C L, BRETSCHER L E, GUZEI I A, et al. Effect of 3-hydroxyproline residues on collagen stability[J]. J Am Chem Soc, 2003, 125(21):6422-6427.
12. HOM R K, GAILUNAS A F, MAMO S, et al. Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human β-secretase[J]. J Med Chem, 2003, 47(1):158-164.
13. MAILLARD M C, HOM R K, BENSON T E, et al. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase[J]. J Med Chem, 2007, 50(4):776-781.
14. RAJAPAKSE H A, NANTERMET P G, SELNICK H G, et al. Discovery of oxadiazoyl tertiaiy carbinamine inhibitors of β-secretase (BALE-1)[J]. J Med Chem, 2006, 49(25):7270-7273.
15. FRESKOS J N, FOBIAN Y M, BENSON T E, et al. Design of potent inhibitors of human beta-secretase. Part 1[J]. Bioorg Med Chem Lett, 2007, 17(1):73-77.
16. HUSSAIN I, HAWKINS J, HARRISON D, et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo[J]. J Neurochem, 2007, 100(3):802-809.
17. CLARKE B, DEMONT E, DINGWALL C, et al. BACE-1 inhibitors part 1:identification of novel hydroxy ethylamines (HEAs)[J]. Bioor Med Chem Lett, 2008, 18(3):1011-1016.
18. CHARRIER N, CLARKE B, CUTLER L, et al. Second generation of hydroxyethylamine BACE-1 inhibitors:optimizing potency and oral bioavailability[J]. J Med Chem, 2008, 51(11):3313-3317.
19. CLARKE B, DEMONT E, DINGWALL C, et al. BACE-1 inhibitors part 2:identification of hydroxyl ethylamines (HEAs) with reduced peptidic character[J]. Bioor Med Chem Lett, 2008, 18(3):1017-1021.
20. BESWICK P, CHARRIER N, CLARKE B, et al. BACE-1 inhibitors part 3:identification of hydroxyl ethylamines (HEAs) with nanomolar potency in cells[J]. Bioor Med Chem Lett, 2008, 18(3):1022-1026.
21. CRAMER R D. Topomer CoMFA:a design methodology for rapid lead optimization[J]. J Med Chem, 2003, 46(3):374-388.
22. IRWIN J J, STERLING T, MYSINGER M M, et al. ZINC:a free tool to discover chemistry for biology[J]. J Chem Inf Model, 2012, 52(7):1757-1768.
23. TEAGUE S J, DAVIS A M, LEESON P D, et al. The design of leadlike combinatorial libraries[J]. Angew Chem Int Ed Engl, 1999, 38(24):3743-3748.
24. JONES G, WILLETT P, GLEN R C. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation[J]. J Mol Biol, 1995, 245(1):43-53.
25. KUNTZ I D, BLANEY J M, OATLEY S J, et al. A geometric approach to macromolecule-ligand interactions[J]. J Mol Biol, 1982, 161(2):269-288.
26. ELDRIDGE M D, MURRAY C W, AUTON T R, et al. Empirical scoring functions:Ⅰ. the development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes[J]. J Comput Aided Mol Des, 1997, 11(5):425-445.
27. MUEGGE I, MARTIN Y C. A general and fast scoring function for protein-ligand interactions:a simplified potential approach[J]. J Med Chem, 1999, 42(5):791-804.
28. CRAMER R D, PATTERSON D E, BUNCE J D. Comparative molecular field analysis (CoMFA). 1. effect of shape on binding of steroids to carrier proteins[J]. J Am Chem Soc, 1988, 110(18):5959-5967.
29. JILEK R J, CRAMER R D. Topomers:a validated protocol for their self-consistent generation[J]. J Chem Inf Comput Sci, 2004, 44(4):1221-1227.
30. CRAMER R D, JILEK R J, ANDREWS K M. Dbtop:topomer similarity searching of conventional structure databases[J]. J Mol Graph Model, 2002, 20(6):447-462.
31. JAIN A N. Scoring noncovalent protein-ligand interactions:a continuous differentiable function tuned to compute binding affinities[J]. J Comput Aided Mol Des. 1996, 10(5):427-440.
32. CLARK R D, STRIZHEV A, LEONARD J M, et al. Consensus scoring for ligand/protein interactions[J]. J Mol Graph Model, 2002, 20(4):281-295.
33. CHARIFSON P S, CORKERY J J, MURCKO M A, et al. Consensus scoring:a method for obtaining improved hit rates from docking databases of three-dimensional structures into proteins[J]. J Med Chem, 1999, 42(25):5100-5109.
34. MANOHARAN P, VIJAYAN R S, GHOSHAL N. Rationalizing fragment based drug discovery for BACE1:insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies[J]. J Comput Aided Mol Des, 2010, 24(10):843-864.

Journal of Biomedical Engineering

Application of an R-group Search Strategy into Three-dimensional Quantitative Structure-activity Relationship of HEA β-secretase Inhibitors and Molecular Virtual Screening

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