A molecular simulation study of hepatitis B virus core protein and the nuclear protein allosteric modulators of phthalazinone derivatives.

Hepatitis B virus, causing hepatitis, cirrhosis, liver failure, and liver cancer, poses a serious threat to human health, and the currently approved drugs still cannot eliminate the virus completely. HBV core protein allosteric modulators (CpAMs) with a phthalazinone structure which targets the HBV core (HBc) protein have been seen as a new kind of drug because of their excellent antiviral effects. This study explores the structure-activity relationship and binding mechanism of phthalazinone molecules through three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics, and binding free energy calculation and decomposition studies. In addition, CoMFA and CoMSIA models revealed that the steric field, the hydrophobic field, and the hydrogen bond acceptor field may play important roles in the binding process. The molecular docking and dynamics disclosed the most likely binding pose of phthalazinone derivatives with the HBc protein. The binding free energy calculation and decomposition analysis indicated that the van der Waals force was the driving force and that ValE124, ThrD109, ThrE128, LeuD140, IleD105, PheD110, ThrD33, and TrpD102 were the key residues. This study provides an important theoretical basis for the design and optimization of phthalazinone compounds.

Molecular docking, 3D-QASR and molecular dynamics simulations of thiazoles Pin1 inhibitors.

Pin1 (protein interacting with never-in-mitosis akinase-1) is a member of the PPIase (peptidylprolyl cis-trans isomerase) family. It can interact with a variety of carcinogenic or tumor suppressive phosphorylated proteins. The interaction results in the conformational changes of target proteins, and ultimately regulates the activity of these proteins. These activity changes play a key role in tumorigenesis. Pin1 is an attractive target for cancer therapy due to its over-expression and/or activation in various types of cancer and the disorder of Proline directed phosphorylation. In this study, molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular dynamics (MD) simulations were performed to investigate the structure-activity relationship and binding mechanism of 45 thiazole-class Pin1 inhibitors. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. The results of the 3 D-QSAR model show that electrostatic field, hydrophobic field and hydrogen bond play important roles in the binding process of inhibitors to protein. Molecular dynamics simulation results reveal that the complex of the ligand and the receptor protein are stable at 300 K. The binding free energy calculation and energy decomposition results show that His59, Cys113, Ser114, Ser115, Leu122, Met130, Gln131, Phe134, Ser154 and His157 may be the key to the inhibitor binding to Pin1 protein. This study provides an important theoretical basis for further development of the new Pin1 inhibitor design. These results can provide more useful information for our further drug design. Communicated by Ramaswamy H. Sarma.

Investigating the binding mechanism of piperidinyl ureas inhibitors based on the UBC12-DCN1 interaction by 3D-QSAR, molecular docking and molecular dynamics simulations.

Neddylation regulates a variety of biological processes by modulating Cullin-RING E3 ubiquitin ligases (CRLs) which is considered to be an important target for human diseases. The activation of CRLs required Cullins Neddylation, which regulated by the interaction of UBC12-DCN1 complex. Here, to investigate the structure-activity relationship and binding mechanism of 41 piperidinyl ureas inhibitors based on the UBC12-DCN1 protein-protein interaction, we carried out molecular modeling studies using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations.Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q2=0.736, r2ncv=0.978, r2pred=0.78 (CoMFA), and the best CoMSIA model has q2=0.761, r2ncv=0.987, r2pred=0.86. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300 K. The results of MM-GBSA indicated the residues of Ile1083, Ile1086, Ala1098, Val1102, Ile1105, Gln1114, Phe1164 and Leu1184 might be the key residues during the process of inhibitors bound to DCN1. This study could provide an important theoretical basis for further developing novel inhibitors design based on UBC12-DCN1 protein-protein interaction. All the results can provide us more useful information for our further drug design. Communicated by Ramaswamy H. Sarma.

Acetic acid transporter-mediated, oral, multifunctional polymer liposomes for oral delivery of docetaxel.

Nanoparticle-structuring aimed at the acetic acid (A) transporter on intestinal epithelial cells and tumor cells is a new potential strategy to enhance oral bioavailability and anti-tumor efficacy. In this study, chitosan (CS) was modified with hydrophilic A and hydrophobic lipoic acid (L), to produce ACSL. A novel ACSL-modified multifunctional liposomes (Lip) loaded with docetaxel (DTX; DTX-ACSL-Lip) was then prepared and characterized. DTX-ACSL-Lip recorded higher pH sensitivity and slower release than DTX-Lip and showed dithiothreitol (DTT) response release. DTX-ACSL-Lip uptake by Caco-2 cells was also significantly enhanced mainly viaA transporters compared with DTX-Lip. ACSL modification of DTX-Lip also improved oral bioavailability by 10.70-folds, with a 3.45-fold increase in Cmax and a 1.19-fold prolongation in retention time of DTX in the blood. Moreover, the grafting degree of A significantly affected cell uptake and oral bioavailability. They also showed a significant (1.33-fold) increase in drug intratumoral distribution, as well as an increase in tumor growth inhibition rate from 54.34% to 87.51% without weight loss, compared with DTX-Lip. Therefore, modification of DTX-Lip with ACSL can significantly enhance the oral bioavailability and anti-tumor efficacy of DTX without obvious toxicity, confirming the potential of the dual strategy of targeting A transporter and controlled drug release in tumor cells in oral therapy of tumor.