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Alicia P. Higueruelo Adrian Schreyer G. Richard J Bickerton Tom L. Blundell Will R. Pitt 《PloS one》2012,7(12)
Efforts to increase affinity in the design of new therapeutic molecules have tended to lead to greater lipophilicity, a factor that is generally agreed to be contributing to the low success rate of new drug candidates. Our aim is to provide a structural perspective to the study of lipophilic efficiency and to compare molecular interactions created over evolutionary time with those designed by humans. We show that natural complexes typically engage in more polar contacts than synthetic molecules bound to proteins. The synthetic molecules also have a higher proportion of unmatched heteroatoms at the interface than the natural sets. These observations suggest that there are lessons to be learnt from Nature, which could help us to improve the characteristics of man-made molecules. In particular, it is possible to increase the density of polar contacts without increasing lipophilicity and this is best achieved early in discovery while molecules remain relatively small. 相似文献
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U O Ugalde A Hernandez I Galindo D Pitt J C Barnes G Wakley 《Journal of general microbiology》1992,138(10):2205-2212
A plasma membrane fraction was obtained by the combined use of differential centrifugation and aqueous polymer two-phase partitioning techniques. Vanadate-inhibited ATPase and glucan synthase activities were highly enriched in this fraction, although the presence of ATPase activity which was not inhibited by vanadate, nitrate, molybdate, anyimycin A or azide was also detected. Other intracellular membrane marker activities were present at very low or undetectable levels. A further separation step using Percoll density gradient centrifugation resulted in the separation of a fraction which exclusively contained vanadate-inhibited ATPase activity, and was enriched with silicotungstic-acid-staining membrane material. Latency tests performed on the plasma membrane markers showed that the membrane vesicles were in the right-side-out orientation. 相似文献
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J. I. Pitt 《Journal of applied microbiology》1989,67(S18):1s-9s
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A method of quantifying bands on polyacrylamide gels based on image processing of digitized photographic negatives is presented. 相似文献
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L Lee R C Webb B Pitt 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1992,200(4):466-471
Dietary supplementation with eicosapentaenoic acid (EPA) alters arachidonate metabolism. This study characterizes the effect of dietary EPA on endothelium-dependent vasodilation to acetylcholine (ACH) and ATP in guinea pig coronary resistance vessels. Guinea pigs were fed standard chow (n = 6), standard chow+sesame seed oil (n = 6), or standard chow+menhaden fish oil (17% EPA; n = 6). Coronary vasodilations were examined in the isolated, potassium-arrested heart utilizing a modified Langendorff preparation. Coronary vessels were constricted with prostaglandin F2 alpha and relaxed with ACH (5.5 x 10(-9)-10(-6) moles) or ATP (10(-10)-10(-7) moles). Endothelium-dependent dilations to ACH, but not ATP, were attenuated by dietary supplementation with EPA. To assess the role of the endothelium in modulating vascular responses to agonists following dietary manipulation, the perfusate was stimulated by electrolysis (9 V, 4 Hz, 2 msec) in order to generate free radicals, which we have shown to preferentially damage the endothelium. After endothelial damage, responses to ACH, ATP, and nitroprusside were similar between the dietary groups. In an additional group of standard diet animals (n = 6) experiments were performed to assess the role of prostanoid metabolism in affecting coronary vascular reactivity. Perfusion of hearts with indomethacin (14 microM) reduced endothelium-dependent vasodilations to ACH (5.5 x 10(-9)-10(-6) moles), but not to ATP (10(-10)-10(-7) moles). After endothelial damage, infusion of ACH resulted in vasoconstriction, whereas vasodilation responses to ATP were absent. We conclude that dietary supplementation with EPA inhibits endothelium-dependent dilations to ACH in guinea pig coronary microvessels. These diet-related differences in vascular reactivity may be related to the fish-oil-induced alteration of vasodilator prostaglandin metabolism. In the coronary bed, different endothelial factors appear to mediate relaxation to ACH and ATP. 相似文献
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The appropriateness of several elastic constitutive laws for apple and potato cell walls is tested using uniform cell inflation data. Whole-tissue stress-strain behavior under uniaxial loading is predicted from an analysis of the compression of a conglomerate of cells in a simple arrangement. 相似文献
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Nuclear magnetic resonance (NMR) spectroscopy was used to study Pseudomonas aeruginosa cytochrome c-551. Assignments of resonances to specific residues have been made. A low-resolution X-ray structure was used to aid assignments. A structural comparison was made between P. aeruginosa cytochrome c-551 and mammalian cytochrome c, based on comparisons of NMR data. 相似文献