Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.

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Abstract:The effect of urbanization on the urban thermal environment (UTE) has attracted increasing research attention for its significant relationship to local climatic change and habitat comfort. Using quantitative thermal remote sensing and spatial statistics methods, here we analyze four Landsat TM/ETM+ images of Guangzhou in South China acquired respectively on 13 October 1990, 2 January 2000, 23 November 2005, and 2 January 2009, to investigate the spatiotemporal variations in the land surface temperature (LST) over five land use/land cover (LULC) types and over different urban/rural zones. The emphases of this study are placed on the urban heat island (UHI) intensity and the relationships among LST, the normalized difference built-up index (NDBI), and the normalized difference vegetation index (NDVI). Results show that: (1) the UHI effect existed obviously over the period from 1990 to 2009 and high temperature anomalies were closely associated with built-up land and densely populated and heavily industrialized districts; (2) the UHI intensities represented by the mean LST difference between the urban OPEN ACCESSRemote Sens. 2012, 4 2034 downtown area and the suburban area were on average 0.88, 0.49, 0.90 and 1.16 K on the four dates, at the 99.99% confidence level; and (3) LST is related positively with NDBI and negatively with NDVI. The spatiotemporal variation of UTE of Guangzhou could be attributed to rapid urbanization, especially to the expanding built-up and developing land, declining vegetation coverage, and strengthening of anthropogenic and industrial activities which generate increasing amounts of waste heat. This study provides useful information for understanding the local climatic and environment changes that occur during rapid urbanization.