Structure-based pharmacophore mapping and virtual screening of natural products to identify polypharmacological inhibitor against c-MET/EGFR/VEGFR-2.

Three receptor tyrosine kinases (RTKs), c-MET, EGFR, and VEGFR-2 have been identified as potential oncogenic targets involved in tumor development, metastasis, and invasion. Designing inhibitors that can simultaneously interact with multiple targets is a promising approach, therefore, inhibiting these three RTKs with a single chemical component might give an effective chemotherapeutic strategy for addressing the disease while limiting adverse effects. The in-silico methods have been developed to identify the polypharmacological inhibitors particularly for drug repurposing and multitarget drug design. Here, to find a viable inhibitor from natural source against these three RTKs, structure-based pharmacophore mapping and virtual screening of SN-II database were carried out. The filtered compound SN00020821, identified as Cedeodarin, from different computational approaches, demonstrated good interactions with all the three targets, c-MET/EGFR/VEGFR-2, with interaction energies of -42.35 kcal/mol, -49.32 kcal/mol and -44.83 kcal/mol, respectively. SN00020821displayed stable key interactions with critical amino acids of all the three receptors' kinase catalytic domains including "DFG motif" explored through the MD simulations. Furthermore, it also met the ADMET requirements and was determined to be drug-like as predicted from the Lipinski's rule of five and Veber's rule. Finally, SN00020821 provides a novel molecular scaffold that could be investigated further as a polypharmacological anticancer therapeutic candidate that targets the three RTKs.Communicated by Ramaswamy H. Sarma.

Crizotinib-induced anti-cancer activity in human cervical carcinoma cells via ROS-dependent mitochondrial depolarization and induction of apoptotic pathway.

INTRODUCTION: Cervical cancer is one of the leading causes of mortality among women population worldwide. In spite of recurrent screening, vaccination, and chemotherapeutic interventions, combating cervical cancer still remains a challenge. Crizotinib is a small molecule inhibitor that targets mesenchymal epithelial transition factor (c-MET) and has been successfully studied for its anti-cancer effects in non-small cell lung cancer, pancreatic, gastric, renal, prostate, and breast carcinomas. Although c-MET is a well-known prognostic, diagnostic, and therapeutic target in cervical cancer, anti-cancer properties of its inhibitor crizotinib against cervical carcinoma, has not been explored yet. METHODS: In the present study, the anti-cancer effects of crizotinib on cervical cancer cells were evaluated using various in vitro cell-based assays, such as labelling drug-treated cells with MTT, H2 DCFDA, Annexin V5-fluorescein isothiocyanate (FITC) antibody, JC-1, PI, and analysis using fluorescence-activated cell sorting (FACS). RESULTS: The molecule was found to effectively inhibit proliferation of cervical cancer cells HeLa and SiHa with an IC50 of 0.641 ± 0.0724 and 0.871 ± 0.104 µM, respectively, and induce apoptosis in a dose-dependent manner. Further investigations showed that crizotinib-induced production of reactive oxygen species (ROS) with increasing concentrations further resulted in mitochondrial membrane depolarization. However, the drug had no effect on cell cycle progression of HeLa and SiHa cells. CONCLUSION: Thus, the study elucidates the cytotoxic effects of crizotinib in cervical cancer cells by activation of ROS-dependent apoptotic pathway via mitochondrial depolarization. These findings will further aid the evaluation of other molecular mechanisms of crizotinib and would pave the way for its implication as a chemotherapeutic option in cervical cancer.

Microbial biofilm ecology, in silico study of quorum sensing receptor-ligand interactions and biofilm mediated bioremediation.

Biofilms are structured microbial communities of single or multiple populations in which microbial cells adhere to a surface and get embedded in extracellular polymeric substances (EPS). This review attempts to explain biofilm architecture, development phases, and forces that drive bacteria to promote biofilm mode of growth. Bacterial chemical communication, also known as Quorum sensing (QS), which involves the production, detection, and response to small molecules called autoinducers, is highlighted. The review also provides a brief outline of interspecies and intraspecies cell-cell communication. Additionally, we have performed docking studies using Discovery Studio 4.0, which has enabled our understanding of the prominent interactions between autoinducers and their receptors in different bacterial species while also scoring their interaction energies. Receptors, such as LuxN (Phosphoreceiver domain and RecA domain), LuxP, and LuxR, interacted with their ligands (AI-1, AI-2, and AHL) with a CDocker interaction energy of - 31.6083 kcal/mole; - 34.5821 kcal/mole, - 48.2226 kcal/mole and - 41.5885 kcal/mole, respectively. Since biofilms are ideal for the remediation of contaminants due to their high microbial biomass and their potential to immobilize pollutants, this article also provides an overview of biofilm-mediated bioremediation.