Combining Mendelian Randomization Analysis and 3D-QSAR to Investigate the Effectiveness of a New Series of Hydroxyquinolines in Osteoarthritis
- Authors: Lian Z.1, Su K.1, Lu H.1, Qu C.1, Ma X.1
-
Affiliations:
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University
- Issue: Vol 31, No 27 (2024)
- Pages: 4392-4405
- Section: Anti-Infectives and Infectious Diseases
- URL: https://permmedjournal.ru/0929-8673/article/view/644981
- DOI: https://doi.org/10.2174/0109298673287134231121050158
- ID: 644981
Cite item
Full Text
Abstract
Background::Osteoarthritis (OA) represents a persistent degenerative joint ailment. As OA advances, profound joint pain coupled with diminished joint function inflicts substantial physical distress and psychological strain on patients. Presently, pharmacological solutions for arthritis remain limited, primarily encompassing analgesics and joint replacement surgical procedures. Hence, non-operative strategies to mitigate osteoarthritis progression have captured significant attention in orthopedic research.
Objective::This study aims to discern a definitive causal linkage between ADAMTS-4/5 and osteoarthritis through Mendelian randomization analysis.
:Moreover, it seeks to anticipate the therapeutic efficacy of a suite of emergent hydroxyquinolines for osteoarthritis using the Quantitative Structure-Activity Relationship (QSAR) methodology.
Methods::Within this study, genetic variants specific to knee osteoarthritis were procured as exposure variables from a genome-wide association study (GWAS). Genetic variant data for ADAMTS-4/5 served as the endpoint to evaluate the causal nexus employing univariate Mendelian randomization. This analysis underpins the hypothesis that ADAMTS-4/5 presents a promising therapeutic target for osteoarthritis management. The suppressive properties of novel hydroxyquinolines against ADAMTS-4/5 were subsequently examined through conformational analyses, underscoring the potential of these compounds as therapeutic candidates for osteoarthritis.
Results::IVW outcomes from the Mendelian randomization revealed a significant association of KOA (OR: 1.1675, 95% CI: 1.0003-1.3627, P = 0.0495) with ADAMTS-5. However, KOA (OR: 1.0801, 95% CI: 0.9256-1.2604, P = 0.3278) displayed no evident connection with ADAMTS-4. Notably, the instrumental variables manifested neither heterogeneity nor horizontal pleiotropy. In this research endeavor, 16 pharmacological models were formulated via the CoMSIA method within 3D conformational relationship evaluations. A synergistic interplay of hydrophobic, spatial, and hydrogen-bonded receptor domains emerged as the most predictively potent. The cross-validation coefficient q2 for the optimum model stood at 0.716, with a principal component score of 5, a regression coefficient r2 of 0.971, a standard estimation error of 0.351, and an f-value of 156.951. Such metrics intimate the commendable predictive prowess of our devised CoMSIA models.
Conclusion::The research unearthed a robust causal interrelation between ADAMTS-5 and osteoarthritis via Mendelian randomization. Furthermore, a credible drug model targeting ADAMTS-5 was constructed. Collectively, these findings illuminate a path forward in the pursuit of target-specific drugs for osteoarthritis management in subsequent investigations.
About the authors
Zheng Lian
Department of Spinal Surgery, The Affiliated Hospital of Qingdao University
Email: info@benthamscience.net
Kunpeng Su
Department of Spinal Surgery, The Affiliated Hospital of Qingdao University
Email: info@benthamscience.net
Hui Lu
Department of Spinal Surgery, The Affiliated Hospital of Qingdao University
Email: info@benthamscience.net
Changpeng Qu
Department of Spinal Surgery, The Affiliated Hospital of Qingdao University
Email: info@benthamscience.net
Xuexiao Ma
Department of Spinal Surgery, The Affiliated Hospital of Qingdao University
Author for correspondence.
Email: info@benthamscience.net
References
- Sinusas, K. Osteoarthritis: Diagnosis and treatment. Am. Fam. Physician, 2012, 85(1), 49-56. PMID: 22230308
- Altman, R; Hackel, J; Niazi, F Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: A systematic review. Seminars in arthritis and rheumatism, 2018, 48(2), 168-175.
- Cilek, M.Z.; de Vega, S.; Shiozawa, J.; Yoshinaga, C.; Miyamae, Y.; Chijiiwa, M.; Mochizuki, S.; Ito, M.; Kaneko, H.; Kaneko, K.; Ishijima, M.; Okada, Y. Synergistic upregulation of ADAMTS4 (aggrecanase-1) by cytokines and its suppression in knee osteoarthritic synovial fibroblasts. Lab. Invest., 2022, 102(1), 102-111. doi: 10.1038/s41374-021-00685-4 PMID: 34718343
- Malemud, C.J. Inhibition of MMPs and ADAM/ADAMTS. Biochem. Pharmacol., 2019, 165, 33-40. doi: 10.1016/j.bcp.2019.02.033 PMID: 30826330
- Santamaria, S. ADAMTS-5: A difficult teenager turning 20. Int. J. Exp. Pathol., 2020, 101(1-2), 4-20. doi: 10.1111/iep.12344 PMID: 32219922
- Wang, J.; Wang, X.; Ding, X.; Huang, T.; Song, D.; Tao, H. EZH2 is associated with cartilage degeneration in osteoarthritis by promoting SDC1 expression via histone methylation of the microRNA-138 promoter. Lab. Invest., 2021, 101(5), 600-611. doi: 10.1038/s41374-021-00532-6 PMID: 33692439
- Ong, M.H.L.; Wong, H.K.; Tengku-Muhammad, T.S.; Choo, Q.C.; Chew, C.H. Pro-atherogenic proteoglycanase ADAMTS-1 is down-regulated by lauric acid through PI3K and JNK signaling pathways in THP-1 derived macrophages. Mol. Biol. Rep., 2019, 46(3), 2631-2641. doi: 10.1007/s11033-019-04661-6 PMID: 30989556
- Gilbert, A.M.; Bursavich, M.G.; Lombardi, S.; Georgiadis, K.E.; Reifenberg, E.; Flannery, C.R.; Morris, E.A. N-((8-Hydroxy-5-substituted-quinolin-7-yl) (phenyl) methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2). Bioorg. Med. Chem. Lett., 2008, 18(24), 6454-6457. doi: 10.1016/j.bmcl.2008.10.065 PMID: 18974001
- Marshall, G.R. Computer-aided drug design. Annu. Rev. Pharmacol. Toxicol., 1987, 27(1), 193-213. doi: 10.1146/annurev.pa.27.040187.001205 PMID: 3555315
- Verma, J.; Khedkar, V.; Coutinho, E. 3D-QSAR in drug design-a review. Curr. Top. Med. Chem., 2010, 10(1), 95-115. doi: 10.2174/156802610790232260 PMID: 19929826
- Emdin, C.A.; Khera, A.V.; Kathiresan, S. Mendelian randomization. JAMA, 2017, 318(19), 1925-1926. doi: 10.1001/jama.2017.17219 PMID: 29164242
- Suhre, K.; Arnold, M.; Bhagwat, A.M.; Cotton, R.J.; Engelke, R.; Raffler, J.; Sarwath, H.; Thareja, G.; Wahl, A.; DeLisle, R.K.; Gold, L.; Pezer, M.; Lauc, G.; El-Din Selim, M.A.; Mook-Kanamori, D.O.; Al-Dous, E.K.; Mohamoud, Y.A.; Malek, J.; Strauch, K.; Grallert, H.; Peters, A.; Kastenmüller, G.; Gieger, C.; Graumann, J. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat. Commun., 2017, 8(1), 14357. doi: 10.1038/ncomms14357 PMID: 28240269
- Bowden, J.; Del Greco M, F.; Minelli, C.; Davey Smith, G.; Sheehan, N.; Thompson, J. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat. Med., 2017, 36(11), 1783-1802. doi: 10.1002/sim.7221 PMID: 28114746
- Burgess, S.; Thompson, S.G. Interpreting findings from mendelian randomization using the MR-Egger method. Eur. J. Epidemiol., 2017, 32(5), 377-389. doi: 10.1007/s10654-017-0255-x PMID: 28527048
- Burgess, S.; Bowden, J.; Fall, T.; Ingelsson, E.; Thompson, S.G. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1), 30-42. doi: 10.1097/EDE.0000000000000559 PMID: 27749700
- Hemani, G.; Tilling, K.; Davey Smith, G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet., 2017, 13(11), e1007081. doi: 10.1371/journal.pgen.1007081 PMID: 29149188
- Yu, Z.; Li, X.; Ge, C.; Si, H.; Cui, L.; Gao, H.; Duan, Y.; Zhai, H. 3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines. Mol. Divers., 2015, 19(1), 135-147. doi: 10.1007/s11030-014-9556-0 PMID: 25355276
- Li, X.; Ye, L.; Wang, X.; Wang, X.; Liu, H.; Qian, X.; Zhu, Y.; Yu, H. Molecular docking, molecular dynamics simulation, and structure-based 3D-QSAR studies on estrogenic activity of hydroxylated polychlorinated biphenyls. Sci. Total Environ., 2012, 441, 230-238. doi: 10.1016/j.scitotenv.2012.08.072 PMID: 23137989
- Klebe, G. Comparative molecular similarity indices analysis: CoMSIAM//3D QSAR in drug design: Recent advances. In: Dordrecht; Springer Netherlands, 1998; pp. 87-104.
- Lian, Z; Si, H; Xia, H Structure-activity relationship study and design of novel 1, 8-naphthimide derivatives as potential DNA-targeting chemotherapeutic agents for osteosarcoma. Med. Chem., 2023, 19(9), 906-914.
- Lian, Z.; Sang, C.; Li, N.; Zhai, H.; Bai, W. 3D,2D-QSAR study and docking of novel quinazolines as potential target drugs for osteosarcoma. Front. Pharmacol., 2023, 14, 1124895. doi: 10.3389/fphar.2023.1124895 PMID: 36895941
- Höskuldsson, A. PLS regression methods. J. Chemometr., 1988, 2(3), 211-228. doi: 10.1002/cem.1180020306
- Pratim Roy, P.; Paul, S.; Mitra, I.; Roy, K. On two novel parameters for validation of predictive QSAR models. Molecules, 2009, 14(5), 1660-1701. doi: 10.3390/molecules14051660 PMID: 19471190
- Wieland, H.A.; Michaelis, M.; Kirschbaum, B.J.; Rudolphi, K.A. Osteoarthritis - an untreatable disease? Nat. Rev. Drug Discov., 2005, 4(4), 331-344. doi: 10.1038/nrd1693 PMID: 15803196
- Sharma, L. Osteoarthritis of the knee. N. Engl. J. Med., 2021, 384(1), 51-59. doi: 10.1056/NEJMcp1903768 PMID: 33406330
- Quicke, J.G.; Conaghan, P.G.; Corp, N.; Peat, G. Osteoarthritis year in review 2021: Epidemiology & therapy. Osteoarthritis Cartilage, 2022, 30(2), 196-206. doi: 10.1016/j.joca.2021.10.003 PMID: 34695571
- Sanchez-Lopez, E.; Coras, R.; Torres, A.; Lane, N.E.; Guma, M. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol., 2022, 18(5), 258-275. doi: 10.1038/s41584-022-00749-9 PMID: 35165404
- de Lange-Brokaar, B.J.E.; Ioan-Facsinay, A.; van Osch, G.J.V.M.; Zuurmond, A.M.; Schoones, J.; Toes, R.E.M.; Huizinga, T.W.J.; Kloppenburg, M. Synovial inflammation, immune cells and their cytokines in osteoarthritis: A review. Osteoarthritis Cartilage, 2012, 20(12), 1484-1499. doi: 10.1016/j.joca.2012.08.027 PMID: 22960092
- Martel-Pelletier, J.; Boileau, C.; Pelletier, J.P.; Roughley, P.J. Cartilage in normal and osteoarthritis conditions. Best Pract. Res. Clin. Rheumatol., 2008, 22(2), 351-384. doi: 10.1016/j.berh.2008.02.001 PMID: 18455690
- Jiang, L.; Lin, J.; Zhao, S.; Wu, J.; Jin, Y.; Yu, L.; Wu, N.; Wu, Z.; Wang, Y.; Lin, M. ADAMTS5 in osteoarthritis: Biological functions, regulatory network, and potential targeting therapies. Front. Mol. Biosci., 2021, 8, 703110. doi: 10.3389/fmolb.2021.703110 PMID: 34434966
- Plaas, A.; Osborn, B.; Yoshihara, Y.; Bai, Y.; Bloom, T.; Nelson, F.; Mikecz, K.; Sandy, J.D. Aggrecanolysis in human osteoarthritis: confocal localization and biochemical characterization of ADAMTS5hyaluronan complexes in articular cartilages. Osteoarthritis Cartilage, 2007, 15(7), 719-734. doi: 10.1016/j.joca.2006.12.008 PMID: 17360199
- Verma, P.; Dalal, K. ADAMTS-4 and ADAMTS-5: Key enzymes in osteoarthritis. J. Cell. Biochem., 2011, 112(12), 3507-3514. doi: 10.1002/jcb.23298 PMID: 21815191
- Rogerson, F.M.; Chung, Y.M.; Deutscher, M.E.; Last, K.; Fosang, A.J. Cytokine-induced increases in ADAMTS-4 messenger RNA expression do not lead to increased aggrecanase activity in ADAMTS-5deficient mice. Arthritis Rheum., 2010, 62(11), 3365-3373. doi: 10.1002/art.27661 PMID: 20662062
- Moncada-Pazos, A.; Obaya, A.J.; Viloria, C.G.; López-Otín, C.; Cal, S. The nutraceutical flavonoid luteolin inhibits ADAMTS-4 and ADAMTS-5 aggrecanase activities. J. Mol. Med. (Berl.), 2011, 89(6), 611-619. doi: 10.1007/s00109-011-0741-7 PMID: 21365186
- Wainwright, S.D.; Bondeson, J.; Hughes, C.E. An alternative spliced transcript of ADAMTS4 is present in human synovium from OA patients. Matrix Biol., 2006, 25(5), 317-320. doi: 10.1016/j.matbio.2006.03.006 PMID: 16723216
- Furtwängler, T.; Chan, S.C.W.; Bahrenberg, G.; Richards, P.J.; Gantenbein-Ritter, B. Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model. Spine, 2013, 38(22), E1377-E1387. doi: 10.1097/BRS.0b013e31829ffde8 PMID: 23778376
- Savić-Gajić, I.M.; Savić, I.M. Drug design strategies with metal-hydroxyquinoline complexes. Expert Opin. Drug Discov., 2020, 15(3), 383-390. doi: 10.1080/17460441.2020.1702964 PMID: 31829757
Supplementary files
