In-silico design of novel myocilin inhibitors for glaucoma therapy

Purpose: To explore newer computational approaches in the design of novel myocilin inhibitors for the treatment of glaucoma.Methods: An in-silico virtual screening technique based on simulation of molecular docking was utilised to design a novel myocilin inhibitors for the treatment of  glaucoma. The designed novel molecules were theoretically evaluated to predict their pharmacokinetic properties and toxic effects. Lead molecules were screened out in virtual screening technique on the basis of low binding energies obtained in AutoDock based molecular docking simulation.Results: Out of ten top lead compounds screened, ZINC01729523 and ZINC04692015 were promising, having shown potent inhibition of myocilin, good pharmacokinetic properties and absence of any toxic effects.Conclusion: In-silico virtual screening of molecular libraries containing a large number of ligands is very useful for short-listing of potential lead molecules for further structure-based discovery of antiglaucoma-drugs.Keywords: Glaucoma, Myocilin, Docking, Virtual-screening, Autodock, Ligand, Drug desig

Improving the Accuracy of Density Functional Theory (DFT) Calculation for Homolysis Bond Dissociation Energies of Y-NO Bond: Generalized Regression Neural Network Based on Grey Relational Analysis and Principal Component Analysis

We propose a generalized regression neural network (GRNN) approach based on grey relational analysis (GRA) and principal component analysis (PCA) (GP-GRNN) to improve the accuracy of density functional theory (DFT) calculation for homolysis bond dissociation energies (BDE) of Y-NO bond. As a demonstration, this combined quantum chemistry calculation with the GP-GRNN approach has been applied to evaluate the homolysis BDE of 92 Y-NO organic molecules. The results show that the ull-descriptor GRNN without GRA and PCA (F-GRNN) and with GRA (G-GRNN) approaches reduce the root-mean-square (RMS) of the calculated homolysis BDE of 92 organic molecules from 5.31 to 0.49 and 0.39 kcal mol−1 for the B3LYP/6-31G (d) calculation. Then the newly developed GP-GRNN approach further reduces the RMS to 0.31 kcal mol−1. Thus, the GP-GRNN correction on top of B3LYP/6-31G (d) can improve the accuracy of calculating the homolysis BDE in quantum chemistry and can predict homolysis BDE which cannot be obtained experimentally

Carvacrol Alleviates Prostate Cancer Cell Proliferation, Migration, and Invasion through Regulation of PI3K/Akt and MAPK Signaling Pathways

TRPM7 is a potential therapeutic target for treatment of prostate cancer. In this study, we investigated the effects of nonselective TRPM7 inhibitor carvacrol on cell proliferation, migration, and invasion of prostate cancer PC-3 and DU145 cells. Our results showed that carvacrol blocked TRPM7-like currents in PC-3 and DU145 cells and reduced their proliferation, migration, and invasion. Moreover, carvacrol treatment significantly decreased MMP-2, p-Akt, and p-ERK1/2 protein expression and inhibited F-actin reorganization. Furthermore, consistently, TRPM7 knockdown reduced prostate cancer cell proliferation, migration, and invasion as well. Our study suggests that carvacrol may have therapeutic potential for the treatment of prostate cancer through its inhibition of TRPM7 channels and suppression of PI3K/Akt and MAPK signaling pathways

Factors affecting reorientation of hydraulically induced fracture during fracturing with oriented perforations in shale gas reservoirs

Hydraulic fracturing with oriented perforations is an effective technology for reservoir stimulation for gas development in shale reservoirs. However, fracture reorientation during fracturing operation can affect the fracture conductivity and hinder the effective production of shale gas. In the present work, a numerical simulation model for investigating fracture reorientation during fracturing with oriented perforations was established, and it was verified to be suitable for all investigations in this paper. Based on this, factors (such as injection rate and fluid viscosity) affecting both of initiation and reorientation of the hydraulically induced fractures were investigated. The investigation results show that the fluid viscosity has little effect on initiation pressure of hydraulically induced fracture during fracturing operation, and the initiation pressure is mainly affected by perforation azimuth, injection rate and the stress difference. Moreover, the investigation results also show that perforation azimuth and difference between two horizontal principle stresses are the two most important factors affecting fracture reorientation. Based on the investigation results, the optimization of fracturing design can be achieved by adjusting some controllable factors. However, the regret is that the research object herein is a single fracture, and the interaction between fractures during fracturing operation needs to be further explored