Non-Hereditary Obesity Type Networks and New Drug Targets: An In Silico Approach.

Obesity, a chronic, preventable disease, has significant comorbidities that are associated with a great human and financial cost for society. The aim of the present work is to reconstruct the interactomes of non-hereditary obesity to highlight recent advances of its pathogenesis, and discover potential therapeutic targets. Obesity and biological-clock-related genes and/or gene products were extracted from the biomedical literature databases PubMed, GeneCards and OMIM. Their interactions were investigated using STRING v11.0 (a database of known and predicted physical and indirect associations among genes/proteins), and a high confidence interaction score of >0.7 was set. We also applied virtual screening to discover natural compounds targeting obesity- and circadian-clock-associated proteins. Two updated and comprehensive interactomes, the (a) stress- and (b) inflammation-induced obesidomes involving 85 and 93 gene/gene products of known and/or predicted interactions with an average node degree of 9.41 and 10.8, respectively, were produced. Moreover, 15 of these were common between the two non-hereditary entities, namely, ADIPOQ, ADRB2/3, CCK, CRH, CXCL8, FOS, GCG, GNRH1, IGF1, INS, LEP, MC4R, NPY and POMC, while phelligridin E, a natural product, may function as a potent FOX1-DBD interaction blocker. Molecular networks may contribute to the understanding of the integrated regulation of energy balance/obesity pathogenesis and may associate chronopharmacology schemes with natural products.

Dual Targeting of DNA Damage Response Proteins Implicated in Cancer Radioresistance.

Ionizing radiation can induce different types of DNA lesions, leading to genomic instability and ultimately cell death. Radiation therapy or radiotherapy, a major modality in cancer treatment, harnesses the genotoxic potential of radiation to target and destroy cancer cells. Nevertheless, cancer cells have the capacity to develop resistance to radiation treatment (radioresistance), which poses a major obstacle in the effective management of cancer. It has been shown that administration of platinum-based drugs to cancer patients can increase tumor radiosensitivity, but despite this, it is associated with severe adverse effects. Several lines of evidence support that activation of the DNA damage response and repair machinery in the irradiated cancer cells enhances radioresistance and cellular survival through the efficient repair of DNA lesions. Therefore, targeting of key DNA damage repair factors would render cancer cells vulnerable to the irradiation effects, increase cancer cell killing, and reduce the risk of side effects on healthy tissue. Herein, we have employed a computer-aided drug design approach for generating ab initio a chemical compound with drug-like properties potentially targeting two proteins implicated in multiple DNA repair pathways. The findings of this study could be taken into consideration in clinical decision-making in terms of co-administering radiation with DNA damage repair factor-based drugs.