Combined e-pharmacophore based screening and docking of PI3 kinase with potential inhibitors from a database of natural compounds.

Sasidhar Reddy Eda

doi:10.6026/97320630015709

Abstract

Phospho inositide 3-kinase (PI3 K) is a promising target for the design of anticancer drugs and is of significant concern in developing selective isoforms as inhibitors for cancer treatments. The results obtained from the computational analysis were selected based on Glide score and drug binding interaction features. Molecular docking studies and prime MM-GBSA energy calculations showed STOCK1N-77648 with optimal binding features for further consideration. The hydrogen bonding patterns between the top three molecules STOCK1N-91335, STOCK1N-70036 and STOCK1N-77648 and the target protein based on G-scores is reported. The STOCK1N-77648 ligand molecule has protein residue interactions similar to that of interactions with the known inhibitor copanlisib. These data illustrates selectivity of the small molecular PI3 K inhibitors through screening and molecular docking for further in vitro and in vivo consideration.

Highlights

Tumor development and invasion are the consequence of malignant transformation; they depend on surrounding stroma environmental influences, local growth factors, and systemic hormones
The hydrogen bonding patterns between the top three molecules STOCK1N-91335, STOCK1N-70036 and STOCK1N-77648 and the target protein based on G-scores is reported
It is believed that the composition of the extra cellular matrix (ECM) affects malignant behaviour that may depend on the differentiation status of tumor cells [1]

Summary

Background

Tumor development and invasion are the consequence of malignant transformation; they depend on surrounding stroma environmental influences, local growth factors, and systemic hormones. Recent studies have shown that cell signalling in transformed cells generated with the aid of growth factors and oncogenes requires collaboration with specific. Multiple survival signals are upregulated on integrin ligation, which includes increased expression of BCl-2 or FlIP ( known as CflAR), activation of the PI3K-AKT pathway or nuclear factor-μB (nF-μB) signalling, and/or p53 inactivation [5]. Integrin engagement with the ECM molecule was shown to be directly mediated by AKT activation via PI3K signalling through the direct recruitment of PI3 K into the subunit [6]. One approach to targeting PPIs is the rational design of small molecules that mimic the interaction at the protein-protein interface of a few key residues. Data helps us to understand potential biomarkers and therapeutic therapies in the fight against defined subpopulations of aggressive tumors and specific α5β1 integrin antagonists that may represent new potential therapeutic agents

Materials and Methods

Results and Discussion

Rule of three