Neela M. Bhatia

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

Graphical abstract Figure. No caption available. HighlightsComputational approach for screening chemically diverse natural products targeting ER+ breast cancer.Virtual screening, QSAR studies and pharmacophores modeling resulted in potential hits.In silico validation of hits using drugs of clinical regime can lead to new small ER‐&agr; modulators. ABSTRACT The steroid, estrogen has been recognized as being important for stimulating the growth of breast cancers primarily mediated via the steroidal estrogen receptor‐&agr; (ER‐&agr;). 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‐&agr; 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‐&agr; 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.

Synthesis, Characterization, Pharmacokinetics and Evaluation of Cytotoxicity for Docetaxel-Oleate Conjugate Targeting MCF-7 Breast Cancer Cells

The present work envisages synthesis of an ester conjugate of anticancer drug docetaxel with oleoyl chloride, with the aim to selectively target the breast cancer cells MCF-7 so as to minimize non-specific hemolytic side effects. The synthesized docetaxel-oleate conjugate was characterized and confirmed by physicochemical and spectral methods. Solubility and partition coefficient determination indicated increased solubility and lipophilicity, while protein binding studies revealed low protein binding capacity of the conjugated drug. Subsequently, the conjugate was evaluated for its in vitro cytotoxicity, drug release, and hemolysis effects. The results indicated a lesser RBC lysis at a more significant anticancer activity of the parent drug and a selective diffusion at pH of cancer cells (compared to the pH of normal cells), thereby increasing specificity and decreasing adverse effects. In addition, an analytical HPLC method was developed for hydrolytic study of the conjugated drug. The proposed method showed good separation of the target compounds with high accuracy and precision. Hydrolysis study indicated a minimum hydrolysis of the conjugate at various pH that simulated gastric and intestinal fluids. Thus, the synthesized conjugate proves to be a useful prodrug in reducing systemic toxicity of docetaxel as well as selectively targeting cancerous cells.

Exploration of Leads from Natural Domain Targeting HER2 in Breast Cancer: An In-Silico Approach

The human epidermal growth factor (HER2/neu) receptor protein target expression plays a vital role in the development of breast cancer and is increased in around 20% of breast cancers. Currently, only two drugs lapatinib and neratinib are approved as HER2 inhibitors. The present in silico studies involves a computational approach for the identification of active compounds from the chemically diverse set of natural products against the HER2/neu receptor. Molecular docking studies facilitated the evaluation of HER2 binding affinity of potential natural product hits. The hits were subjected to binding interaction analysis in comparison with HER2 inhibitors and other tyrosine kinase inhibitors to get an idea about why only neratinib and lapatinib specifically target HER2. It was found that only these two drugs exhibited charge interaction with the amino acid residue ASP863, which was absent in case of other tyrosine kinase inhibitors. Furthermore, the results revealed 22 potential hits, amongst which six anthocyanidins, one alkaloid, and an acid derivative were found to inhibit the HER2 putatively, and that these compounds can be developed as anticancer drugs in the near future. The remaining 14 compounds that belonged to the benzo-gamma-pyrone class inhibited the tyrosine kinase in silico, which on a structural modification for interacting with ASP863, could serve as potential leads in the drug discovery process as HER2 inhibitors. Additionally, a pharmacophore model was established to investigate the pharmacophoric features of the explored scaffolds for HER2 inhibitory activity.