Isoform-specific Pharmacophore Analysis And Virtual Screening To PI3K

PI3K is a key node regulating the PI3K/AKT/mTOR signaling transduction pathway of several essential biological processes. It has been proved that PI3Ks are potential targets for chemical therapy, especially PI3Ka as one of the most important targets of anti-tumours. Many PI3K inhibitors have been in early clinic development currently. However,they are limited for the lack of selectivity as well as chemical types. Accordingly, it’s important to develop novel isoform-specific inhibitors targeting to PI3Ks.In the first part of this thesis, molecular docking method was applied in PI3Ka-based virtual screening. Combined stratege of drug-like principle filter, virtual screening workflow, multi-scoring methods and structure-diversity analysis was used to screening more than8million compounds of chemical library, and at last105candidates were obtained with novel and diverse structures.The another work in second part is isoform-specific pharmacophore characteristics analysis. Sequence-alignment and structure-alignment as well as ligand-based and structure-based pharmacophore modeling were performed in the study. The pharmacophore analysis showed that H-bond was the crucial for inhibitors targeting to PI3K and three characteristics of H-bond were identified. Hydrophobic characteristics in the central active site, particularly aromatic characteristics are necessary for activity. Analysis for ligand-receptor interaction and pharmacophore confirmed that inhibitor’s interaction with P-loop is a key point for selectivity.In this thesis, the information obtained from computer aided drug design method including virtual screening and pharmacophore analysis is helpful to develop novel PI3K inhibitors.