Use of the tubulin bound paclitaxel conformation for structure-based rational drug design

A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.     

The acoustic features of vervet monkey alarm calls

Vervet monkeys routinely produce semantic alarm calls upon detection of various predators encountered in their natural environment. Two of these calls, snake and eagle alarms, were analyzed using digital signal processing techniques in order to identify potentially distinctive acoustic cues. Distinctive cues were sought in the periodicity of the source waveform associated with each call type, the probable vocal tract filtering functions, and in temporal patterning. Results were equivocal with respect to source periodicity, but a variety of distinguishing features were found in both supralaryngeal filtering and timing. These data provide a basis for psychoacoustic perceptual testing with vervets as subjects.     

Optimized Dropping and Rolling (ODR) method for packing of poly-disperse spheres

Powder-based microstructures are traditionally modelled using densely packed spherical particles. In this letter, a new dropping and rolling packing algorithm is employed by means of analytical equations, to investigate the random packing of spherical particles. The three-dimensional randomly packed microstructures are quantified in terms of packing density and computational time.