In silico identification of sclerostin inhibitors.

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.