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Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q2 = 0.828, r2 = 0.988, r2pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r2 = 0.968, r2pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs. [ABSTRACT FROM AUTHOR]

An important task of the China Fusion Engineering Test Reactor physics design is to develop operation scenarios with high fusion power (1 GW), high bootstrap current fraction for steady-state and a plasma edge compatible with heat and particle exhaust. To achieve these goals, triangularity (δ) effects on the fusion performance of two candidate scenarios, with or without reversed magnetic shear (RS), namely conventional H-mode and RS H-mode, are evaluated using core-edge coupled integrated modeling in this paper. For fixed pedestal density, it is shown that higher δ is favorable for higher fusion performance in the conventional H-mode scenario while the fusion performance decreases with increasing δ in the RS H-mode scenario. In conventional H-mode, the higher fusion performance at high δ mainly comes from a higher pedestal temperature as predicted by EPED in combination with stiff core kinetic profiles. In the RS H-mode scenario with a local reversed shear region, the profiles are non-stiff and a strong internal transport barrier (ITB) exists at low δ. This results in higher density and temperature inside the ITB for low δ, leading to higher fusion power. If the pedestal temperature is kept fixed, in both scenarios the significant increase in pedestal density, which extends into the core, dominates at high δ and leads to much higher fusion power. For conventional H-mode, destabilization from increasing δ is partially balanced by stabilization due to increasing ν*. Since the normalized heat sources are quite similar, it results in minimal changes in the temperature profiles except for the lowest density case. For RS H-mode, destabilization from increasing δ is approximately balanced by stabilization due to increasing ν* in foot region, but a strong temperature ITB is still evident for low δ. The ability to take advantage of the high pedestal density in conventional H-mode and reversed shear scenario depends on its compatibility with edge density requirements from efficient heat and particle exhaust. Transport analysis is presented to elucidate the roles of δ, collisionality and magnetic shear in altering the profiles and the ITB, which contribute to the different behavior in the two scenarios. [ABSTRACT FROM AUTHOR]