Total views : 159
Computational Regression and Prediction Analysis on a Dataset of 52 Pyrrolo[2,3-b]Pyridines and Pyrimidines Rheumatoid Arthritis Inhibitors
Objectives: To evaluate the dependency of physico-chemical properties of a set of BTK inhibitors on activity by linear regression analysis. Methods/Statistical Analysis: A multivariate regression analysis was implemented on 52 Pyrrolo[2,3-b]pyridines and pyrimidines which are reported as Bruton's Tyrosine Kinase (BTK) inhibitors to construct a regression model using complete data set in the relationship between dependent variable and independent variable was estimated using python based regression analysis. Leverages were calculated in order to exclude outlying data from analysis Findings: A linear regression analysis on a complete dataset of BTK inhibitors as dependent variables and few independent variables resulted in F-test: 4.87, r value: 0.737 and r2 value of 0.543, respectively. The dataset investigated for the existence of outliers resulted in 50 BTK inhibitors after excluding 4q and 4zd from the dataset which resulted in improved r2 of 0.701 with better statistics. Further 44 compound training set resulted in improved r and r2 coefficients such as r: 0.816 and r2: 0.666, respectively and applying on a 6 compound validation set which determines regression model reliability and significance. Application/Improvements: Application of regression model to screen novel compounds with decreased H-bond acceptors, logP and KAlpha2 followed by an increase in KAlpha3 and randic index would enhance inhibitory activity against BTK. 1. Introduction Rheumatoid Arthritis (RA) is an autoimmune disease categorized by auto antibody circulation in plasma, inflammation in synovial, destruction of cartilage and bone etc.1,2 Bruton's Tyrosine Kinase (BTK) belongs to Tec kinase member family of enzymes which are necessary for activation of B-cells.3 A designated function for BTK is found in activation of cells mediated by BCR and cell survival.4-6 Compounds which inhibit BTK are known to hinder B cell receptor signaling7, several such inhibitors are currently in clinical trials and the first BTK inhibitor Ibrutinib was approved for treating mantle cell lymphoma. 8 Efforts from medicinal chemistry, synthesis, crystallography has led to the discovery of some non-covalent BTK inhibitory compounds. Several BTK inhibitors such as Pyrrolo[2,3-b]pyridines9, Pyrrolo[2,3-d]pyrimidines10, thieno[3,2-c]pyridin-4-amines11, phenylpyridin-2(1H)- ones12, Imidazo[1,5-a]quinoxalines13, Purine derivatives14, CarbazoleCarboxamides15, PyridazinoneAnalogs16, Diaminopyrimidines17, imidazo[1,5‑a]pyrazines18 are reported. In this paper, linear regression analysis was implemented to study the dependency of physico-chemical properties on
Bruton’s Tyrosine Kinase, Computational Regression, Python, Pyrrolo[2,3-b]Pyridines, Pyrimidines, Rheumatoid Arthritis.
- Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001; 358(9285): 903–91.
- McInnes LB, Schett G. The pathogenesis of rheumatoid arthritis. New England Journal of Medicine. 2011 Dec; 365(23): 2205–19. Crossref PMid:22150039
- Khan WN. Regulation of B lymphocyte development and activation by Bruton’s tyrosine kinase. Immunol Research. 2001 Apr; 23(2-3): 147–56. Crossref
- Khan WN, Alt FW, Gerstein RM. Defective B cell development and function in Btk-deficient mice. Immunity. 1995 Sep; 3(3): 283–99. Crossref
- Kerner JD, Appleby MW, Mohr RN. Impaired expansion of mouse B cell progenitors lacking Btk. Immunity. 1995 Sep; 3(3): 301–12.: Crossref
- Satterthwaite AB, Willis F, Kanchanastit P. A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton’s tyrosine kinase. ProcNatlAcadScience U S A. 2000 Jun; 97(12): 6687–92. Crossref PMCid:PMC18703
- Chang BY, Huang MM, Francesco M. The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Research Theory. 2011; 13(4): 115. Crossref PMid:21752263 PMCid:PMC3239353
- Advani RH, Buggy JJ, Sharman JP. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of Clinical Oncology. 2013; 31(1): 88–94. Crossref PMid:23045577
- Zhao X, Huang W, Wang Y, Xin M, Jin Q, Cai J, Tang F, Zhao Y, Xiang H. Pyrrolo [2, 3-b] pyridine derivatives as potent Bruton’s tyrosine kinase inhibitors. Bioorganic and medicinal chemistry. 2015 Aug; 23(15): pp. 4344-53. Crossref PMid:26169764
- Zhao X, Huang W, Wang Y, Xin M, Jin Q, Cai J, Tang F, Zhao Y, Xiang H. Discovery of novel Bruton’s tyrosine kinase (BTK) inhibitors bearing a pyrrolo [2, 3-d] pyrimidine scaffold. Bioorganic and medicinal chemistry. 2015 Feb; 23(4): 891–901. Crossref PMid:25596757
- Zhao X, Xin M, Wang Y, Huang W, Jin Q, Tang F, Wu G, Zhao Y, Xiang H. Discovery of thieno [3, 2-c] pyridin4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors. Bioorganic and medicinal chemistry. 2015 Sep; 23(17): 6059–68. Crossref PMid:26277759
- Zhao X, Xin M, Huang W, Ren Y, Jin Q, Tang F, Jiang H, Wang Y, Yang J, Mo S, Xiang H. Design, synthesis and evaluation of novel 5-phenylpyridin-2 (1H)-one derivatives as potent reversible Bruton’s tyrosine kinase inhibitors. Bioorganic and medicinal chemistry. 2015 Jan; 23(2): 348– 64. Crossref PMid:25515957
- Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, Lin L, Li E, Keegan S, Lussier J, Wrocklage C. Imidazo [1, 5-a] quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis. Bioorganic and medicinal chemistry letters. 2011 Nov; 21(21): 6258–63. Crossref PMid:21958547
- Shi Q, Tebben A, Dyckman AJ, Li H, Liu C, Lin J, Spergel S, Burke JR, McIntyre KW, Olini GC, Strnad J. Purine derivatives as potent Bruton’s tyrosine kinase (BTK) inhibitors for autoimmune diseases. Bioorganic and medicinal chemistry letters. 2014 May; 24(9): 2206–11. Crossref PMid:24685542
- Liu Q, Batt DG, Lippy JS, Surti N, Tebben AJ, Muckelbauer JK, Chen L, An Y, Chang C, Pokross M, Yang Z. Design and synthesis of carbazolecarboxamides as promising inhibitors of Bruton’s tyrosine kinase (BTK) and Janus kinase 2 (JAK2). Bioorganic and medicinal chemistry letters. 2015 Oct; 25(19): 4265–9. Crossref PMid:26320619
- Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Eigenbrot C, Gallion S, Johnson AR, Kropf JE, Lee SH. Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinoneanalogs with improved metabolic stability. Bioorganic and medicinal chemistry letters. 2016 Jan; 26(2): 575–9. Crossref PMid:26675441
- Huang Z, Zhang Q, Yan L, Zhong G, Zhang L, Tan X, Wang Y. Approaching the active conformation of 1, 3-diaminopyrimidine based covalent inhibitors of Bruton’s tyrosine kinase for treatment of Rheumatoid arthritis. Bioorganic and medicinal chemistry letters. 2016 Apr; 26(8): 1954–7. Crossref PMid:26976214
- Liu J, Guiadeen D, Krikorian A, Gao X, Wang J, Boga SB, Alhassan AB, Yu Y, Vaccaro H, Liu S, Yang C. Discovery of 8-amino-imidazo [1, 5-a] pyrazines as reversible BTK inhibitors for the treatment of rheumatoid arthritis. ACS Medicinal Chemistry Letters. 2015 Dec; 7(2): 198–203. Crossref PMid:26985298 PMCid:PMC4753550
- Jaworska J, Nikolova-Jeliazkova N, Aldenberg T. QSAR applicabilty domain estimation by projection of the training set descriptor space: a review. Alternate Laboratory Animation. 2005; 33: 445–59. PMid:16268757
- Afantitis A, Melagraki G, Sarimveis H, Koutentis PA, Markopoulos J, Igglessi-Markopoulou O. Investigation of substituent effect of 1-(3,3-diphenylpropyl)-piperidinylphenylacetamides on CCR5 binding affinity using QSAR and virtual screening techniques. Journal of Computation Aided Molecule. 2006; 20: 83–95. Crossref PMid:16783600
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution 3.0 License.