Abstract
A series of imidazolium salt derivatives have demonstrated potent antitumor activity in prior research. A comprehensive in silicon method was carried out to identify the putative protein target and detailed structure-activity relationship of the compounds. The Topomer CoMFA and CoMSIA techniques were implemented during the investigation to obtain the relationship between the properties of the substituent group and the contour map of around 77 compounds; the Topomer CoMFA and CoMSIA models were reliable with the statistical data. The protein–protein interaction network was constructed by combining the Pharmmapper platform and STRING database. After generating the sub-network, the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA with protein data bank ID: 3ZIM) was selected as the putative target of imidazolium salt derivatives. A docking study was carried out to correlate interactions of amino acids in protein active pockets surrounded by the ligand with contour maps generated by the structure-activity relationship method. Then the molecular dynamics simulations demonstrated that the imidazolium salt derivatives have potent binding capacity and stability to receptor 3ZIM, and the two ligand-receptor complex was stable in the last 2 ns. Finally, the ligand-based structure-activity relationship and receptor-based docking were combined together to identify the structural requirement of the imidazolium salt derivatives, which will be used to design and synthesize the novel PIK3CA inhibitors.
Highlights
Cancer is the second leading cause of death, globally, and was responsible for 8.8 million deaths in 2015
Cancer-related protein PIK3CA was identified as the putative target for a series of imidazolium salt derivatives by the PharmMapper platform and PPI network
In the following QSAR and docking study, the important substituent groups related to the cytotoxic activity formed molecular interaction directly with the key amino acids around the active pocket; further molecular dynamics (MD) simulations showed the docking conformation to have potent binding affinity and stability
Summary
Cancer is the second leading cause of death, globally, and was responsible for 8.8 million deaths in 2015. Nearly 1 in 6 deaths are due to cancer [1]. Chemotherapy is generally the main treatment for various cancers. Chemotherapeutic agents (anti-cancer drugs) have a range of side-effects such as immunosuppression, myelosuppression, anemia, teratogenicity, infertility, and even secondary neoplasm [2,3,4,5,6]. The major goal of oncology scientists is to design a selective and effective anticancer agent that is only sensitive in normal cancer cells, as well as the ability to predict, alter, or block the hallmark of cancer cells and is likely to improve the therapeutic index [7]. The search for a targeted, effective drug with minimum toxicity is urgently necessary [3,7]
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