Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

INTRODUCTION: Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. METHODS: Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. RESULTS: Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. CONCLUSION: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

Development of leads targeting ER-α in breast cancer: An in silico exploration from natural domain.

The steroid, estrogen has been recognized as being important for stimulating the growth of breast cancers primarily mediated via the steroidal estrogen receptor-α (ER-α). Inhibition of estrogen activity by small molecules with increased target specificity has proven to be an effective treatment for breast cancer. After the success stories of SERMs and fulvestrant, there is a need for the development of new small molecule modulating ER-α is due to developing resistance and side effects to current breast cancer therapy. In this pursuit, we virtually screened 227 chemically diverse bioactive natural products to get the best hits having an ER-α binding affinity. The docking scores and protein-ligand interactions of the obtained hits were emulated with the clinically used selective estrogen modulators and ER-antagonists. The results revealed 18 potential hits, which were putatively classified as hits belonging to ER agonists, modulators, and antagonists. Furthermore, as most of the hits were found to comprise the chromene nucleus, the 2D and 3D QSAR studies were performed using a set of natural products and synthesized compounds containing this scaffold, to understand the structural requirements for improving activity against breast cancer. Additionally, a pharmacophore model was generated to investigate the pharmacophoric features of the explored scaffolds for an optimal anticancer activity. The results signify that these compounds with structural modification could serve as potential leads in the drug discovery process for the treatment of breast cancer.