Identification of Repurposed FDA Drugs by Targeting Sclerostin via the Wnt Pathway for Alveolar Bone Formation

Abstract

Objective Natural wingless-related integration site (Wnt) pathway antagonist sclerostin (SOST) has attracted much attention because unusual bone illnesses characterized by the increased bone mass result from its absence of action. The Wnt ligand is prevented from attaching to the Frizzled family receptor when SOST is present. In the active destruction complex, -catenin is phosphorylated. -Catenin molecules do not enter the nucleus and are broken down by a proteasome. As a result, Wnt-responsive genes are not activated, which lowers bone formation and raises bone resorption. A humanized monoclonal antibody called romosozumab binds to and inhibits SOST with significant cardiac side effects. As a result, the current study's objective is to find and screen Food and Drug Administration (FDA) medications that target SOST.

Materials and Methods SOST's structure was retrieved from Protein Data Bank (PDB) (ID: 6l6r). Pharmacophore modeling and molecular operating environment-based virtual testing of FDA-approved medicines. Using the Desmond program, docking and molecular dynamics simulations were performed.

Results Our findings revealed medications with FDA approval (ZINC000253387843) Amphotericin B. The stability and receptor–ligand interactions are pretty substantial, as demonstrated by the findings of docking and Molecular dynamics simulations, which have a docking score of −7.3 k/mol and root mean square deviation stability at 40 nanoseconds, respectively.

Conclusion The suggested pharmacological therapy shows promise since it uses the Wnt pathway to target the primary bone formation mechanism. However, additional prospective studies are required to apply the available data to clinical practice.

Keywords

bone remodeling - sclerostin - periodontal disease - Wnt pathway - osteoblast

Publication History

Article published online:
26 March 2024

• References

• 1 Brent MB, Brüel A, Thomsen JS. Anti-sclerostin antibodies and abaloparatide have additive effects when used as a countermeasure against disuse osteopenia in female rats. Bone 2022; 160: 116417
• 2 Ramli FF, Chin K-Y. A review of the potential application of osteocyte-related biomarkers, fibroblast growth factor-23, sclerostin, and Dickkopf-1 in predicting osteoporosis and fractures. Diagnostics (Basel) 2020; 10 (03) 145
• 3 Balemans W, Van Den Ende J, Freire Paes-Alves A. et al. Localization of the gene for sclerosteosis to the Van Buchem disease-gene region on chromosome 17q12-q21. Am J Hum Genet 1999; 64 (06) 1661-1669
• 4 Hu B, Li Y, Wang M. et al. Functional reconstruction of critical-sized load-bearing bone defects using a Sclerostin-targeting miR-210-3p-based construct to enhance osteogenic activity. Acta Biomater 2018; 76: 275-282
• 5 Van Hul W, Balemans W, Van Hul E. et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet 1998; 62 (02) 391-399
• 6 Yu S, Li D, Zhang N. et al. Drug discovery of sclerostin inhibitors. Acta Pharm Sin B 2022; 12 (05) 2150-2170
• 7 Yan Y, Tang D, Chen M. et al. Axin2 controls bone remodeling through the β-catenin-BMP signaling pathway in adult mice. J Cell Sci 2009; 122 (Pt 19): 3566-3578
• 8 Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 2012; 33 (05) 747-783
• 9 Witcher PC, Miner SE, Horan DJ. et al. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight 2018; 3 (11) e98673
• 10 Sutherland MK, Geoghegan JC, Yu C. et al. Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone 2004; 35 (04) 828-835
• 11 Shu R, Bai D, Sheu T. et al. Sclerostin promotes bone remodeling in the process of tooth movement. PLoS ONE 2017; 12 (01) e0167312
• 12 Li X, Ominsky MS, Niu QT. et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008; 23 (06) 860-869
• 13 Qi J, Liu E, Guo Y-F. et al. Association between periodontal disease and osteoporosis in postmenopausal women: a protocol for systematic review and meta-analysis. BMJ Open 2021; 11 (09) e049277
• 14 Hong S-J, Yang B-E, Yoo D-M, Kim S-J, Choi H-G, Byun S-H. Analysis of the relationship between periodontitis and osteoporosis/fractures: a cross-sectional study. BMC Oral Health 2021; 21 (01) 125
• 15 Esfahanian V, Shamami MS, Shamami MS. Relationship between osteoporosis and periodontal disease: review of the literature. J Dent (Tehran) 2012; 9 (04) 256-264
• 16 Martínez-Maestre MÁ, González-Cejudo C, Machuca G, Torrejón R, Castelo-Branco C. Periodontitis and osteoporosis: a systematic review. Climacteric 2010; 13 (06) 523-529
• 17 Liao C, Ou Y, Wu Y, Zhou Y, Liang S, Wang Y. Sclerostin inhibits odontogenic differentiation of human pulp-derived odontoblast-like cells under mechanical stress. J Cell Physiol 2019; 234 (11) 20779-20789
• 18 Liu M, Kurimoto P, Zhang J. et al. Sclerostin and DKK1 inhibition preserves and augments alveolar bone volume and architecture in rats with alveolar bone loss. J Dent Res 2018; 97 (09) 1031-1038
• 19 Yao Y, Kauffmann F, Maekawa S. et al. Sclerostin antibody stimulates periodontal regeneration in large alveolar bone defects. Sci Rep 2020; 10 (01) 16217
• 20 Brown JP, Prince RL, Deal C. et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009; 24 (01) 153-161
• 21 Lv F, Cai X, Yang W. et al. Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: Systematic review and meta- analysis. Bone 2020; 130: 115121
• 22 Saag KG, Petersen J, Brandi ML. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017; 377 (15) 1417-1427
• 23 Minisola S. Romosozumab: from basic to clinical aspects. Expert Opin Biol Ther 2014; 14 (09) 1225-1228
• 24 Cosman F, Crittenden DB, Adachi JD. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016; 375 (16) 1532-1543
• 25 Sahoo BM, Ravi Kumar BVV, Sruti J, Mahapatra MK, Banik BK, Borah P. Drug repurposing strategy (DRS): emerging approach to identify potential therapeutics for treatment of novel coronavirus infection. Front Mol Biosci 2021; 8: 628144
• 26 Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules 2015; 20 (07) 13384-13421
• 27 Rasheed MA, Iqbal MN, Saddick S. et al. Identification of lead compounds against Scm (fms10) in Enterococcus faecium using computer aided drug designing. Life (Basel) 2021; 11 (02) 77
• 28 Hildebrand PW, Rose AS, Tiemann JKS. Bringing molecular dynamics simulation data into view. Trends Biochem Sci 2019; 44 (11) 902-913
• 29 Salo-Ahen OM, Alanko I, Bhadane R. et al. Molecular dynamics simulations in drug discovery and pharmaceutical development. Processes (Basel) 2020; 9 (01) 71
• 30 Muthusamy K, Mohan S, Nagamani S, Kesavan C. Identification of novel small molecules that bind to the loop2 region of sclerostin - an in silico computational analysis. Physiol Res 2016; 65 (05) 871-878
• 31 Yooin W, Saenjum C, Ruangsuriya J, Jiranusornkul S. Discovery of potential sclerostin inhibitors from plants with loop2 region of sclerostin inhibition by interacting with residues outside Pro-Asn-Ala-Ile-Gly motif. J Biomol Struct Dyn 2020; 38 (05) 1272-1282
• 32 Choi J, Lee K, Kang M, Lim S-K, Tai No K. In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors. Bioorg Med Chem Lett 2018; 28 (06) 1116-1121
• 33 Chandra A, Rajawat J. Skeletal aging and osteoporosis: mechanisms and therapeutics. Int J Mol Sci 2021; 22 (07) 3553