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Published on: May 12, 2017
In silico identification of sclerostin inhibitors
Yusuf Şimşek1, Sahra Setenay Baran2, Erdal Ergünol3
1Vocational School of Health Services, Gazi University, Ankara, 06830, Türkiye. yusufsimsek@gazi.edu.tr.
Abstract:
Wnt/β-catenin signaling pathway plays a major role in the regulation of bone homeostasis. Sclerostin exhibits a high-affinity binding to the Wnt co-receptors LRP5/6 and therefore acts as an extracellular inhibitor of canonical Wnt signaling. Disruption of the interaction between LRP5/6 and sclerostin is essential for Wnt-related metabolic processes that can affect bone health. Consequently, we targeted the loop 2 region of sclerostin, which binds stably to LRP5/6, and employed a series of in silico approaches, including molecular docking and molecular dynamics simulations, to screen drug-like compounds from the DrugBank database. The loop 2 region of sclerostin is relatively flexible and mobile in solution. To enhance the accuracy of screening, we generated eight distinct conformers of sclerostin following initial molecular dynamics simulations. Subsequently, we applied virtual screening methods, including high-throughput virtual screening, standard precision, extra precision, and molecular mechanics generalized Born surface area calculations for each conformer. After merging hits, 50 compounds were further studied with molecular dynamics simulations and binding energy computations over the trajectories. Our results revealed that the compounds DB02675, DB15238, DB04226, DB03325, and DB05644 exhibit inhibitory activity on the loop 2 region of sclerostin.
Insights
Researchers identified five drug compounds that inhibit sclerostin, a key regulator of bone homeostasis. These compounds target the loop 2 region, potentially offering new therapeutic strategies for bone health by modulating Wnt/β-catenin signaling.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Wnt/β-catenin signaling is crucial for maintaining bone homeostasis.
- Sclerostin inhibits Wnt signaling by binding to LRP5/6 co-receptors, impacting bone health.
- Disrupting sclerostin-LRP5/6 interaction is vital for Wnt-related metabolic processes affecting bone.
Purpose of the Study:
- To identify novel drug-like compounds that inhibit sclerostin's interaction with LRP5/6.
- To target the loop 2 region of sclerostin for potential therapeutic intervention.
- To explore in silico methods for screening potential inhibitors of sclerostin.
Main Methods:
- Utilized molecular docking and molecular dynamics simulations to screen DrugBank compounds.
- Generated eight distinct conformers of sclerostin to account for loop 2 flexibility.
- Applied virtual screening (HTVS, SP, XP) and MM/GBSA calculations for hit identification.
- Conducted further molecular dynamics simulations and binding energy computations on selected compounds.
Main Results:
- Identified five compounds (DB02675, DB15238, DB04226, DB03325, DB05644) with inhibitory activity against sclerostin's loop 2 region.
- Confirmed the inhibitory potential of these compounds through molecular dynamics and binding energy analysis.
- Demonstrated the feasibility of using in silico screening for identifying sclerostin inhibitors.
Conclusions:
- The identified compounds show promise as inhibitors of sclerostin.
- Targeting sclerostin's loop 2 region is a viable strategy for modulating Wnt signaling.
- These findings provide a foundation for developing new therapeutics for bone metabolic disorders.
