An in-silico approach to the potential modulatory effect of taurine on sclerostin (SOST) and its probable role during osteoporosis

AbstractThe cysteine-knot containing negative regulator of the Wnt (Wingless-related integration site) signaling pathway, sclerostin (SOST) is an emerging therapeutic target for osteoporosis. Its inhibition is responsible for the promotion of osteoblastogenesis. In this study, taurine, an amino sulfonic acid was used to study its mechanism of action for the inhibition of the SOST protein. Molecular docking and dynamic studies were performed as a part of the study whereby, it was observed that taurine binds to a probable allosteric pocket which allows it to modulate the structure of the SOST protein affecting all of the loops – loops 1, loop 2, and loop 3 – as well as the cysteine residues forming the cysteine-knot. The study also identified a set of seven taurine analogues that have better pharmacological activity than their parent compound using screening techniques. The conclusions derived from the study support that taurine has a probable antagonistic effect on the SOST protein directly through the modulation of HNQS motif and loops 2 and 3 and indirectly through its influence on the cysteine residues - 134, 165 and 167 C. Based on the results, it can be assumed that the binding of taurine with SOST protein probably reduces its binding affinity to the LRP6 protein greatly, while also inhibiting the target protein from anchoring to LRP4. Furthermore, it was noted that probable additional binding with any small molecule inhibitor (SMI) at the active site (PNAIG motif), in the presence of an already allosterically bound taurine, of the SOST protein would result in a complete potential antagonism of the target protein. Additionally, the study also uncovers the possible role of the GKWWRPS motif in providing stability to the PNAIG motif for the purpose of binding with LRP6.Communicated by Ramaswamy H. SarmaKeywords: Sclerostinin-silico studytaurinemolecular dockingmolecular dynamicsanti-sclerostin compoundssmall molecule inhibitorstaurine analoguesView correction statement:Correction AcknowledgmentsThe author (AM) acknowledges Vellore Institute of Technology (VIT) for providing a Teaching cum Research Assistant (TRA) fellowship as financial support.Authors' contributionsAM dealt with conceptualization, data curation, formal analysis, investigation, methodology, software, writing—original draft preparation, and resources. AM and IM were jointly responsible for validation and writing—review & editing. IM supervised, administered the project, and acquired necessary funding as and when required.Data availability statementAll relevant data are within the paper, and its Supporting Information files. The raw data used and/or analyzed during the current study are available from the corresponding author on reasonable request.Disclosure statementThe author(s) declare that they have no competing interests.Related manuscriptsThe author(s) declare that they have no related or duplicate manuscripts under consideration (or accepted) for publication elsewhere.Additional informationFundingThe author(s) received no specific funding for this work.