Pharmacophore Modelling, Virtual Screening, Docking and ADMET Studies of PI3K Inhibitors for theTreament of Cancer

Abstract

Cancer is the second leading causes of deaths worldwide. Nearly 24% of total deaths worldwide are due to cancer. Cancer refers to group of diseases which are marked by rapid proliferation of cells which leads to tumour formation. PI3k are group of enzymes that are responsible for cell proliferation, differentiation and cell growth. Signals from the growth factors activate the tyrosine kinase receptors or the G protein coupled receptors which activates the downstream signalling of AKT and m-TOR. PI3K signalling pathway is responsible for cell growth and survival. PI3K enzymes are capable of phosphorylating the –OH group of phosphotidylinositol at various sites. Mutations at various sites in this signaling pathway lead to excessive cell proliferation and inhibition of apoptosis leading to cancer. Therefore PI3K can be targeted to develop anticancer agent. There are various pi3k inhibitors approved by FDA like LY294002 and Wortmannin. The first marketed pi3k inhibitors are LY294002 and Wortannin. Wortmannin was the first naturally derived from a fungus Penicillium funiculosum and is a non specific inhibitor of pi3k. LY294002 was the first synthetic agent containing a morpholine ring and is a potent pi3k inhibitor. But both of these agents are nonspecific in their action and have low bioavailability. As they play role in cell proliferation they can be suitable target for cancer therapy. The aim is to generate a new molecule that can be identified as a potent hit and can be designed into a lead molecule having activity more than the reference molecule (FDA approved drug) and can be synthesised and can enter the clinical trials.