The beta-secretase is one of prospective targets against Alzheimer's disease (AD). A three-dimensional quan titative structure-activity relationship (3D-QSAR) model of Hydroethylamines (HEAs) as beta-secretase inhibitors was established using Topomer CoMFA. The multiple correlation coefficient of fitting, cross validation and external validation were r2 = 0.928, q(loo)2 = 0.605 and r(pred)2 = 0.626, respectively. The 3D-QSAR model was used to search R groups from ZINC database as the source of structural fragments. As a result, a series of R groups with relatively high activity contribution was obtained to design a total of 15 new compounds, with higher activity than that of the template molecule. The molecular docking was employed to study the interaction mode between the new compounds as ligands and beta-secretase as receptors, displaying that hydrogen bond and hydrophobicity played important roles in the binding affinity between the new compounds and beta-secretase. The results showed that Topomer CoMFA and To pomer Search could be effectively used to screen and design new molecules of HEAs as beta-secretase inhibitors, and the designed compounds could provide new candidates for drug design targeting AD.
Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Drug Design ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Molecular Docking Simulation ; Quantitative Structure-Activity Relationship

OBJECTIVE:To study 3D-QSAR of pyridine heterocyclic ring PI3K inhibitor as anti-renal cancer drug,and to provide reference for the design and R&D of new anti-renal cancer inhibitors. METHODS:The data of structure and active value (pIC50) of 30 pyridine heterocyclic ring PI3K inhibitors were collected. After Sybyl-X 1.1 software used for molecular superimposition, CoMFA and CoMSIA model were established to investigate three dimensional field, electrostatic field, hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field of PI3K inhibitor molecule. Sybyl-X 1.1 software was used for molecular docking,and the mechanism of PI3K inhibitor molecule and receptor target protein were analyzed. PyMOL V1.5 software was used to design new PI3K inhibitor molecules. The activity of inhibitor molecules was predicted with CoMFA and CoMSIA model. RESULTS:The cross validation coefficients of CoMFA and CoMSIA model were 0.617 and 0.601, fitting validation coefficients were 0.969 and 0.974,and external predictive correlation coefficients were 0.656 and 0.670, respectively. In CoMFA model, contributions of three dimensional field and electrostatic field were 56.2% and 43.8%respectively. In CoMSIA model,contributions of three dimensional field,electrostatic field,hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field were 41.0%,31.3%,21.1%,2.4%,4.2%. After molecular superimposition,small steric hindrance,strong positive and hydrophilic groups introduced nearby R1 group of common skeleton could help to enhance the activity of molecules. The results of molecular docking showed that PI3K inhibitor molecule formed three hydrogen bonds with the key amino acids ALA805,VAL882 and THR887 of receptor target protein,with the length of 1.84,1.99,1.99 ?. According to above information,6 new molecules were designed,among which predicted pIC50 of 2 molecules with higher activity were 3.211,3.247(CoMFA method)and 3.238,3.222(CoMSIA method). CONCLUSIONS:Established new CoMFA and CoMSIA model have good prediction ability and statistical stability. Contribution of three dimensional field is higher than that of electrostatic field,and the influence of hydrophobic field on molecular activity can not be ignored. Pyridine heterocyclic ring PI3K inhibitors have strong hydrogen bonding role with receptor target protein. 3D-QSAR can provide reference for the design,reconstruction and drug R&D of new PI3K inhibitor molecule.