Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers.

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110γ and p110δ are evolutionarily divergent; they probably need separate strategies for drug development.

Structural insights into the extra cellular segment of integrinß5 and molecular interaction studies.

Primary tumor cells often spread to other organs by metastasis. Despite of it, primary tumor cells break their surrounding extra cellular matrix (ECM) proteins and reach the destination organ by the process of intravasation and extravasation. Metastasized tumor cells induce the process of angiogenesis, this highly regulated process involves several ECM proteins. However, integrins are primarily involved in the blood vessel growth and repair. Therefore, integrins are promising angiogenesis targets. Integrins are receptors on cell surface, involved in signal transduction and attachments in extra cellular matrix (ECM). IntegrinαVß3 and αVß5 are implicated in tumor angiogenesis, metastasis, inflammation and bone resorption. The crystal structure of integrinαvß5 is not available in protein structural databases, therefore; molecular model of integrinß5 structure was prepared and stereo chemical model quality was checked. Integrin ß5 active sites were identified based on insilico analysis tools. Further, molecular level interactions between integrinß5 and ECM proteins were predicted. In the present study ECM proteins such as focal adhesion kinase 1 (FAK1), annexin A5 and P21 activated kinase 4 (PAK4) were considered for protein-protein docking, to understand inter molecular interactions. The predicted model is conceived to be stereo chemically good and can be used for molecular interaction studies of angiogenic inhibitors.