{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T17:26:27Z","timestamp":1782321987635,"version":"3.54.5"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T00:00:00Z","timestamp":1663545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Zoledronic acid (ZOL) inhibits receptor activator of nuclear factor-\u03baB ligand (RANKL) and reduces bone turnover. This plays an important role in the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Previous reports have shown that ZOL binds to the enzyme farnesyl pyrophosphate synthase (FPPS) to block its activity. However, the mechanism of action of ZOL and its interaction with RANKL is still unclear. In this study, we confirmed that ZOL significantly suppressed the bone remodeling in ZOL-treated rats, investigated whether ZOL could bind to RANKL and examined the interactions between these molecules at the atomic level. Surface plasmon resonance (SPR) assay was performed to validate that ZOL could directly bind to RANKL in a dose dependent manner, and the equilibrium constant was calculated (K<jats:sub>D<\/jats:sub>= 2.28 \u00d7 10<jats:sup>\u22124<\/jats:sup>\u00a0M). Then, we used molecular docking simulation to predict the binding site and analyze the binding characteristics of ZOL and RANKL. Through molecular dynamics simulation, we confirmed the stable binding between ZOL and RANKL and observed their dynamic interactions over time. Binding free energy calculations and its decomposition were conducted to obtain the binding free energy \u221270.67 \u00b1 2.62\u00a0kJ\/mol for the RANKL\u2013ZOL complex. We identified the key residues of RANKL in the binding region, and these included Tyr217(A), Val277(A), Gly278(A), Val277(B), Gly278(B), and Tyr215(C). Taken together, our results demonstrated the direct interaction between ZOL and RANKL, indicating that the pharmacological action of ZOL might be closely related to RANKL. The design of novel small molecules targeting RANKL might reduce the occurrence of BRONJ.<\/jats:p>","DOI":"10.3389\/fmolb.2022.992473","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T05:14:59Z","timestamp":1663564499000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Structural insights into the binding of zoledronic acid with RANKL via computational simulations"],"prefix":"10.3389","volume":"9","author":[{"given":"Ruijie","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duohong","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"116184","DOI":"10.1016\/j.bone.2021.116184","article-title":"Preclinical models of medication-related osteonecrosis of the jaw (MRONJ)","volume":"153","author":"Aguirre","year":"2021","journal-title":"Bone"},{"key":"B2","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1159\/000151371","article-title":"Bisphosphonates and osteonecrosis of the jaw: Moving from the bedside to the bench","volume":"189","author":"Allen","year":"2009","journal-title":"Cells Tissues Organs"},{"key":"B3","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.bone.2010.11.020","article-title":"Denosumab and bisphosphonates: Different mechanisms of action and effects","volume":"48","author":"Baron","year":"2011","journal-title":"Bone"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/cmdc.201700462","article-title":"Porphyrin derivatives inhibit the interaction between receptor activator of NF-\u03baB and its ligand","volume":"12","author":"Chypre","year":"2017","journal-title":"ChemMedChem"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4678","DOI":"10.1021\/acs.jcim.9b00428","article-title":"Protein preparation automatic protocol for high-throughput inverse virtual screening: Accelerating the target identification by computational methods","volume":"59","author":"De Vita","year":"2019","journal-title":"J. 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