Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein

Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle

Value of research findings to the research director

In IDL-535

Lactation performance of goats and growth rates of kids under different milking and rearing methods in Kenya

AbstractTwo experiments were conducted to test different milking procedures for dual-purpose goats that would be suitable for smallholder farmers. In experiment 1, 105 East African and Galla does that kidded to singles were randomly assigned to three treatments: (a) milking in absence of kid and kid sucking residual; (b) milking in presence of kid and kid sucking residual; and (c) milking once a week and kid sucking all milk 6 days of the week. In experiment 2, 45 Galla does that kidded to singles were randomly assigned to three treatments: (a) weigh-suckle-weigh; (b) milking half udder while kid sucking other half and (c) kid sucking all milk in the evening and milking mornings. Measurements of milk yield, milk sucked and weights of kids were taken for 12 weeks of lactation.Results were analysed using least-squares techniques for unequal subclass numbers. Milking in the presence of kids increased does' milk yield. This increase was attributed to the stimulation of milk let-down by the presence of kids. Although this method potentially provided most milk for dairy use, less residual milk was left to sustain growth of kids. Estimates of total milk yield by milking once a week underestimated milk yield potential of the East African and Galla breeds. Results indicated an appropriate method for estimating milk potential should combine both milked and sucked milk measurements. Restricting milk available to the kids reduced their growth rates and thus indirectly affected their maturing rates. No milking procedure proved to be superior all-around for the smallholder for milking goats. To resolve this dilemma, use of an optimizing technique including socio-economic weighting of milk for family use relative to milk for kids was proposed.</jats:p

Health and productivity of East African Zebu under village management in a tsetse area on the coast of Kenya

Evaluates the health and productivity of East African Zebu cattle under village management in a tse-tse infested area surrounding the Muhaka Forest on the Kenya Coast south of Mombassa, and assesses the cost-effectiveness of intervention with trypanocidal drugs