###### Abstract  
Osteoporosis is a complex bone disease indicating porous bone with low bone mass density and fragility. Cathepsin K, V-ATPase, and \(\alpha\
u\beta_{3}\) integrin are exhibited as novel targets for osteoporosis treatment. Our preliminary study uses a state-of-the-art method, including target-based virtual screening and clustering methods to determine promising candidates with multitarget properties. Phytochemicals with osteoprotective properties from the literature are used to elucidate the molecular interactions toward three targets. The binding scores of compounds are normalized and rescored. The K-means and hierarchical clustering methods are applied to filter and define the promising compounds, and the silhouette analysis is supposed to validate the clustering method. We explore 108 herbal compounds by virtual screening and the cluster approach, and find that rutin, sagittatoside A, icarin, and kaempferirtin showed strong binding affinities against Cathepsin K, V-ATPase, and \(\alpha\
u\beta_{3}\) integrin. Dockings of candidates toward three targets also provide the protein-ligand interactions and crucial amino acids for binding. Our study provides a straightforward and less time-consuming approach to exploring the new multitarget candidates for further investigations, using a combination of in silico methods. C 2022 20  
lysosomes with V-ATPase in their membrane fuse with the specialized membrane of osteoclasts and then release the degrading enzymes and proton ion into the bone-resorbing compartment [8; 9]. Cathepsin K is a lysosomal protease enzyme that mainly degrades type I collagen and elastin in the bone matrix at a low pH environment [10; 11]. The inhibition of Cathepsin K suppresses the osteoclast function without impairing its viability, indicating the benefits over current medicines [12]. The current medicines used in the treatment of osteoporosis are bisphosphonates, such as alendronate, which are targeted in the reduction of the bone resorption rate. However, bisphosphonates exhibited several side effects and interrupted the bone remodeling process by induced cell death in osteoclasts. The alternative medicines for osteoporosis treatment are herbal medicines, especially traditional Chinese medicines (TCMs). The use of medicinal plants and natural products in traditional and modern therapy are gaining more interest nowadays. Many studies exhibited that medicinal plants exert their therapeutic potential due to a synergistic effect from a combination of phytochemicals [13; 14; 15]. It was suggested that natural products tend to possess multitarget activity, and less toxicity than synthetic compounds and therefore are potentially a useful starting point for multitarget drug discovery. Additionally, the use of current medicines in osteoporosis treatment may be limited with the treatment period. Polyphenols were extensively investigated, according to their wide variety of efficacies on human health, including antioxidative, anti-inflammatory, anticancer properties, and prevention of cardiovascular diseases, neurodegenerative, and osteoporosis [16; 17; 18]. Polyphenols, specifically flavonoids, possess a positive impact on bone health. The possible mechanisms of polyphenols to balance bone metabolism are due to their anti-oxidative and anti-inflammatory properties, relevant to the number of phenol groups [19]. Multitarget drug discovery is a new paradigm in drug design and development [20]. The multitarget approach has been increasingly interesting for complex disease drug development recently, particularly cancer and Alzheimer's disease [21]. Conceptually, multitarget agents possessing modest activity at more clinically relevant targets may produce similar or better in vivo bioactivities than high target-selective compounds [22]. Several in silico methods were applied to find multitarget candidates.