Cyclooxygenase-2 identified as a potential target for novel radiomodulator scopolamine methyl bromide: An in silico study

Abstract

Background: The lack of a safe and effective drug against radiation injury is a major hurdle in management of these diseases. Owing to unprecedented radionuclear threats and accidents that may occur, screening of Johns Hopkins Clinical Compound Library (JHCCL) was carried out in zebrafish embryos for identifying novel radio modulators against lethal radiation injury and death. This repositioning strategy with the Food and Drug Administration (FDA) approved small molecules identified scopolamine methyl bromide (SMB) as a novel radioprotective and mitigative agent against 20 Gy gamma irradiation dose. The present study is an attempt to identify the potential target of SMB, which may also prove beneficial as a therapeutic target for other SMB like molecules in ameliorating radiation induced injury and death. Method: We have performed in silico studies with structural similarity search tool, using Tanimoto coefficient (Tc) index for identification of a molecule amongst known radioprotectors that acts as the lead reference compound and helps predict SMB activity. A similar analysis with JHCCL was done to predict and identify more SMB like molecules that may contribute to radiomodulation in a similar manner. Further, molecular docking was performed on computational AutoDock Vina platform to predict the novel target for SMB, with identified lead from the known radiomodulators (RM) as the reference compound. DUD-E decoys were used as benchmark for validating our virtual studies. Results: A structural analysis of SMB with JHCCL and collection of known radioprotectors has revealed its close resemblance to atropine, a known radioprotector. It exhibited Tc index of 0.66. Four more structural entities were found from JHCCL bearing close structural resemblance to SMB and atropine. Molecular docking studies performed with muscarinic receptor M2 (reported target of atropine) exhibited similar binding energies (BEs) for atropine and SMB (−9.4 and −9.7 kcal/mol respectively), and a three-dimensional superimposed binding conformation of SMB and atropine. Due to known activity of atropine as an anti-inflammatory agent and as Cyclooxygenase-2 (Cox-2) antagonist, SMB when evaluated for antagonism against Cox-2 receptor exhibited novel inhibitory action. SMB exhibited BE similar to indomethacin (chosen as the reference lead), an established radioprotector due to its potent Cox-2 inhibitory activity. Molecular docking studies revealed similar binding conformation of SMB and indomethacin with BE of −8.0 and −8.2 kcal/mol respectively. DUD-E study further validated SMB to behave as an active ligand for antagonizing Cox-2 in comparison to the decoys. Conclusion: These results emphasised that SMB could be a potent non-steroidal anti-inflammatory agent contributing towards radioprotection/mitigation by inhibiting Cox-2.

Keywords

• Scopolamine methyl bromide
• Antagonist
• Cyclooxygenase-2 (Cox-2)