An In silico Approach to Identify High Affinity Small Molecule Targeting m-TOR Inhibitors for the Clinical Treatment of Breast Cancer

Breast cancer is the most frequent malignancy among women. It is a heterogeneous disease with different subtypes defined by its hormone receptor. A hormone receptor is mainly concerned with the progression of the PI3K/AKT/ mTOR pathway which is often dysregulated in breast cancer. This is a major signaling pathway that controls the activities such as cell growth, cell division, and cell proliferation. The present study aims to suppress mTOR protein by its various inhibitors and to select one with the highest binding affinity to the receptor protein. Out of 40 inhibitors of mTOR against breast cancer, SF1126 was identified to have the best docking score of -8.705, using Schrodinger Suite which was further subjected for high throughput screening to obtain best similar compound using Lipinski's filters. The compound obtained after virtual screening, ID: ZINC85569445 is seen to have the highest affinity with the target protein mTOR. The same result based on the binding free energy analysis using MM-GBSA showed that the compound ZINC85569445 to have the the highest binding free energy. The next study of interaction between the ligand and receptor protein with the pharmacophore mapping showed the best conjugates, and the ZINC85569445 can be further studied for future benefits of treatment of breast cancer.

Computer-aided Drug Designing for the Identification of High-Affinity Small Molecule Targeting CD20 for the Clinical Treatment of Chronic Lymphocytic Leukemia (CLL).

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a B-lineage lymphoid malignancy of self-reactive cells that are focused to produce polyreactive natural autoantibodies. Its surface protein marker CD20 plays an important role in the humoral immune response targeting which has emerged as an attractive therapeutic option for the treatment of CLL. The present study explains the interaction of the CD20 with its established inhibitors and to discover the compound having high binding affinity against the target protein receptor. Technically, during the development of new compound through docking studies, best drug among all pre-exist drugs got filtered, hence in reference to docked best drug study moved ahead. METHODS: The 3D structure of CD20 was built using homology base fold recognition method using Smith waterman's Local alignment and standalone Delta Blast algorithms. 23 established inhibitors towards CD20 were selected in this present investigation. Among these inhibitors, etoposide (RMSD value -96.6481) showed high binding capacity with the receptor CD20 which was further subjected to virtual screening. The said screening presented 380 possible drugs having structural similarity to etoposide. RESULTS: The docking studies of the screened drugs separated the compound having PubChem CID: 11753896 (RMSD value -98.5416). Toxicity and interaction profile validated this compound for having a better affinity with the target protein. Conclusively, this research study says that according to ADMET profile and BOILED-Egg plot, the compound (PubChem CID: 11753896) obtained from Virtual Screen could be the best drug in future during the prevention of Chronic Lymphocytic Leukemia. CONCLUSION: The compound identified in the present investigation can be subjected further for in vitro and in vivo studies for ADMET properties and it could optimize a good profile in the field of pharmacy and bioavailable for suppressing cancer. The pharmacophore study revealed that the drug CID11753896 is a non-inhibitor of CYP450 microsomal enzymes and was found to be non-toxic, similar to the established compound CID36462. It has a lower LD50 value of 2.5423mol/kg as compared to the established compound whose LD50 value is 2.9588mol/kg. Also, the compound was found to be non-carcinogenic.

Structure-Based Virtual Screening for the Identification of High Affinity Compounds as Potent VEGFR2 Inhibitors for the Treatment of Renal Cell Carcinoma.

INTRODUCTION: Renal Cell Carcinoma is a common type of renal cancer-causing deaths worldwide which is characterized by sustained angiogenesis. VEGF and its receptors play a major role in physiologic and pathologic angiogenesis, which is marked in tumour progression and metastasis development. Induction of VEGF genes occur due to hypoxic condition induced by tumour growth after a critical size in cancerous cell. Signal transduction networks originated by VEGFA/VEGFR2, (a notable ligand-receptor complex in the VEGF system) leads to major angiogenesis events ranging from endothelial cell proliferation, to new vessel formation, Furthermore, differential expression of VEGF-VEGFR mRNA also found in different types of RCC. AIM: The aim of present study is to inhibit the VEGFR2 protein by the action of certain inhibitors and then to search an efficient inhibitor. MATERIALS AND METHODS: A total of 23 potential inhibitors were searched and used to target the protein using the concept of molecular docking. Among 23 inhibitors, CHEMBL346631 shows best affinity with the target protein and was used for high throughput virtual screening to find similar compounds. The compound obtained from virtual screeningSCHEMBL469307, shows much more better affinity with VEGFR2 than CHEMBL346631. CONCLUSION: Relative study for both the compounds showed a minor difference in relevant properties. The compound SCHEMBL469307 have a high potential to inhibit the VGFR2 protein and can be backed for future studies in Renal Cell Carcinoma.