Small Molecules to perturb

Experimental strategies designed around small molecule inhibitors have been critical in advancing our understanding ofbiological mechanisms. This chapter introduces a series ofbiological questions and illustrates how they have been addressed by using small molecules to perturb protein function. 

Van der Waals interactions between identical solid particles are always attractive [7]. However, if the Hamaker constant of the suspending fluid is intermediate between the Hamaker constants of two different particles, the van der Waals interactions will be repulsive [9]. Moreover, in view of the finite speed of propagation of electromagnetic radiation, the response of a molecule to perturbations in the electric field deriving from another nearby molecule is not instantaneous. Retardation effects are observable at separation distances as small as 1 or 2 nm, and they become prominent at larger distances (>10 nm) [50]. Gregory [50] has proposed a simple expression for describing retarded van der Waals interactions between flat plates ... 

This study provides evidence that Rab prenylation is important to statin-induced muscle toxicity, and that it is possible to identify suppressive small molecules that should not inhibit the beneficial effects of statins on blood cholesterol levels. The use of small molecules to dissect biosynthetic pathways is certainly not new, but affords a precise and rapid understanding of the phenotypic consequences of cellular perturbations. For the future, modern chemical biology techniques, including affinity labeling of isoprenoids [11], provide an attractive opportunity to identify the specific Rabs responsible for statin-induced muscle toxicity. As a common laboratory tool compound, G66976 is unlikely to become a clinical candidate. 

The ability of small molecules to interact with biological macromolecules such as proteins in a selective, often reversible, and dose-dependent manner, and to exert specific effects, has led to them being regarded as powerful tools for the study of biological systems. The use of small molecules in this manner to selectively perturb biological function underpins the whole of medicinal chemistry as well as forming the basis for the field of chemical genetics. ... 

The carpanone-based hbrary was screened to discover small molecules that perturb a secretory pathway that involves the transport of properly folded proteins from the endoplasmic reticulum (ER) through the Golgi apparatus to the plasma membrane. Whole-cell fluorescence imaging with temperature-sensitive vesicular stomatitis virus glycoprotein fused to green fluorescent protein (VSVGts-GFP) ... 

Vibrational energy states are too well separated to contribute much to the entropy or the energy of small molecules at ordinary temperatures, but for higher temperatures this may not be so, and both internal entropy and energy changes may occur due to changes in vibrational levels on adsoiption. From a somewhat different point of view, it is clear that even in physical adsorption, adsorbate molecules should be polarized on the surface (see Section VI-8), and in chemisorption more drastic perturbations should occur. Thus internal bond energies of adsorbed molecules may be affected. 

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