Identification of novel inhibitors of P13K/AKT pathways: an integrated in-silico study towards the development of a new therapeutic agent against ovarian cancer

Abstract

Abstract Ovarian cancer is a crucial gynaecological unmet medical disease with a high mortality rate. According to recent research, the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways are hyper-activated in the majority of ovarian cancer patients, necessitating the use of inhibitors. Over the years, phytochemicals have been used as alternative sources of therapeutic agents due to their reported biological activities and limited side effects. Curcuma longa (Tumeric), a reported ayurvedic medicine has also been noted for its anti-cancer properties. Thus, 155 phytochemicals from this plant and 2 reference drugs were evaluated for their inhibitory prowess against P13K/AKT receptor using a computer-aided drug design approach. The binding scores and inhibiting efficiencies were obtained via virtual screening. Molinspiration Chemoinformatics and SwissADME tools were used to investigate the drug-likeness properties and oral bioavailability of the compounds selected, while the ADMET SAR-2 website was used to conduct the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Other analyses performed on the selected compounds include bioactivity, activity spectra for substances (PASS) prediction, binding mode, and molecular interaction. The results revealed that Hopenone 1 (−8.8 kcal mol−1) and Epriprocurcumenol (−7.8 kcal mol−1) are potent inhibitors of the P13K receptor, while Epiprocurcumenol (−9.0 kcal mol−1), Procurcuminol (−8.6 kcal mol−1) and Curlone (−8.3 kcal mol−1) are potential inhibitors of AKT receptor. In comparison to Topotecan and Melphalan, they have better binding affinities, oral bioavailability, drug-likeness characteristics, ADMET properties, bioactivities, PASS properties, binding mechanism, and also interact well with the active site of the target receptor. As a result, this preliminary investigation suggests that these chemicals should be studied further for the design of novel ovarian cancer therapeutics.