Physical activity in prevention of cancer and better prognosis

Cancer is a multifactorial disease with genetic and environmental risk factors. Environmental factors may also be termed as modifiable risk factors and these contribute towards 35% of cancer related mortalities as reported by World Health Organization. Obesity is the leading risk factor in this regard, causing not only deaths due to cancer but also to many other diseases. Among different factors causing obesity, a major contributor is lack of physical activity. In this era of modern technology and digitalization, sedentary mode of life has become a part of life and is mostly unavoidable. At the same time, there is a rise in the incidence of cancer. In the olden times, people used to do all manual work, a lot of walk, exercise and had healthy life style. Such healthy life style may have prevented them from various diseases.             Physical activity as a therapy on daily basis, is associated with a reduction in incidence of various carcinomas. It may improve overall wellbeing of healthy people as well as diseases persons from various ailments. As it is a common proverb that, “prevention is better than cure”, physical activity serves as a preventive measure for various diseases and also for fitness of normal healthy people. Although it is a known fact, yet planned population studies are required to provide evidence. Instead of unorganized physical activities, a structured physical activity may help in improvement of condition of cancer patients, prevention of cancer, cancer related deaths as well we quality of life. Healthcare providers should guide the patients in this regard.             There is lack of awareness among physicians and mostly they don’t refer them to physical therapists. There is also lack of information regarding the implementation of the programs and regimens of physical exercises for different diseases and cancers. Physical therapists may guide the patients in terms of frequency, intensity, duration of exercises which may serve as a betterment of their condition.

Combined Ligand and Structure Based Studies on Modulators of Akt Kinases

Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ). Akt isoforms emerged as anti-cancer drug targets because of their constitutive hyperactivation in various oncological disorders. However, due to high intra-family similarity within ATP binding region, the development of isoform-selective modulators of Akt represent a challenging endeavor and thus, until now only a handful of compounds were selected for the clinical investigation. Yet none of them could reach the market for routine clinical use due to their off-target toxicity and poor pharmacokinetic properties. Recent reports on achieving isoform selectivity by designing inhibitors against less conserved pleckstrin homology (PH) domain offer the opportunity to reduce the major off-target toxic effects of Akt antagonists. Therefore, in this thesis, combined ligand- and structure-based in silico strategies have been utilized to probe the key structural features for the inhibition of the PH domain of Akt2 which is more commonly overexpressed in solid tumors. Toward this end, various predictive 2DQSAR (two-dimensional quantitative structure-activity relationship) and GridIndependent Molecular Descriptor (GRIND) and pharmacophore models using structurally diverse data set of 111 quinoline analogs have been developed. Our key findings demonstrate that the presence of three hydrogen bond donors (D1-D3) at a molecular distance of ~8.4, 21.6, 16.8 Å between D1–D2, D1–D3 and D2–D3, respectively is important for selective inhibition of PH domain of Akt2. In addition, our docking results indicated a crucial role of Lys30 for the optimal fit of quinoline-type inhibitors within the binding cavity of the Akt2 PH domain. Moreover, the structurebased pharmacophore model exhibited three hydrogen bond acceptors (A1-A3) at a distance of 4.05 Å (A1-A2), 11.58 Å (A2-A3) and 15.33 Å (A1-A3) that are complementary to the molecular distances identified by GRIND which further validate the reliability of our developed models. Additionally, identified hits through pharmacophoric-based virtual screening provided a new arsenal of potentially selective chemical scaffolds which have a broad structural diversity and less chemical similarity to any of the other known Akt2-PH domain inhibitors. Subsequently, selectivity profiling with the help of proteochemometric modeling revealed essential substructures such as Nmethylpent-3-en-2-amine for selective inhibition of Akt1, methylene amine, isoproenylterazol and 2H-tetrazole for Akt2, and formaldehyde hydrazine for the Akt3 selective inhibition. The present work also illustrates the substructure based similarity search of ChemBridge database to identify Akt2-selective hit compounds. In the present study, one of the selected carboxamide-type hit showed 1.2 and 2.1 fold selectivity against Akt2 as compared to Akt1 and Akt3, respectively. Overall, the work described in this thesis could pave the way towards the identification of potential modulators of Akt2 against cell proliferation in cancer with high isoform-selectivity and limited side effects.