4-Hydroxytamoxifen (4-OHT), the most common hormone used for the treatment of breast cancer, is a selective estrogen receptor modulator (SERM) inhibitor that acts as an antagonist in breast tissue and a partial agonist in the endometrium. However, the detailed molecular mechanism of 4-OHT structure modification has not been well investigated to date. Herein, molecular docking, molecular dynamics simulations and free energy calculations were performed to explore the mechanisms of the molecular interactions between newly designed benzophenone imines (BIs) and the three forms apo, antagonist and agonist of the human estrogen receptor hERα. The proposed inhibitors were designed by replacing the triarylethylene estrogenic scaffold found in 4-OHT with Schiff base triarylimine derivatives. The antiestrogen scaffold i.e. the O-alkyl side chain in 4-OHT was developed by incorporating an alanine amino acid side chain functionality into the triarylimine scaffold. Docking results reveal that the newly designed BIs bind to the hydrophobic open pocket of the apo and antagonist hERα conformations with higher affinity as compared to the natural and synthetic estrogen estradiol (E2) and 4-OHT. The analysis of the molecular dynamics simulation results based on six different systems of the best docked BI (5c) with hERα receptors demonstrates stable interactions, and the complex undergoes fewer conformational fluctuations in the open apo/antagonist hERα receptors as compared to the case of the closed agonist. In addition, the calculated binding free energies indicate that the main factor that contributes to the stabilization of the receptor-inhibitor complexes is hydrophobic interactions. This study suggests that the development of these Schiff base derivatives may be worth exploring for the preparation of new 4-OHT analogues.
During last decades, 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thione scaffold remains the center of interest due to their ease of preparation, diverse range substituents at N-3 and N-5 positions, and profound biological activities. In the current study, a series of 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thiones were synthesized in good to excellent yield, and the structure of the compounds were confirmed by various spectroscopic techniques such as FTIR, 1H-NMR, 13C-NMR and Mass spectrometry, and finally evaluated against Leishmania major. Whereas, all the evaluated compounds (1-33), demonstrate potential leishmanicidal activities with IC50 values in the range of (1.30- 149.98 uM). Among the evaluated compounds such as 3, 4, 6, and 10 exhibited excellent leishmanicidal activities with IC50 values of (2.17 μM), (2.39 μM), (2.00 μM), and (1.39 μM), respectively even better than the standard amphotericin B (IC50 = 0.50) and pentamidine (IC50 = 7.52). In order to investigate binding interaction of the most active compounds, molecular docking study was conducted with Leishmania major. Further molecular dynamic simulation study was also carried out to assess the stability and correct binding of the most active compound 10, within active site of the Leishamania major. Likewise, the physiochemical properties, drug likeness, and ADMET of the most active compounds were investigated, it was found that none of the compounds violate Lipiniski's rule of five, which show that this class of compounds had enough potential to be used as drug candidate in near future.Communicated by Ramaswamy H. Sarma.