Mapping transporter substrates

ALTERNATIVE PRODUCT INHIBITION ABORTIVE COMPLEXES ALTERNATIVE SUBSTRATES COMPETITIVE INHIBITOR ABORTIVE COMPLEXES MAPPING SUBSTRATE INTERACTIONS USING KINETIC DATA MEMBRANE TRANSPORT ENERGY OF ACTIVATION Old... 

The BCRP is an ABC transporter similar to P-gp whose expression results in resistance to anticancer therapeutics and may limit intestinal absorption of drugs. However, there have been limited studies to elucidate the selectivities of dmgs for P-gp and BCRP (Brooks et al. 2004). We used a published dataset of seven topoisomerase inhibitors (Maliepaard et al. 2001) to construct a HipHop model for BCRP. We then mapped the potent tyrosine kinase inhibitor Gleevec to this pharmacophore as this compound has been suggested experimentally in conflicting studies as both a substrate and inhibitor of BCRP (Burger et al. 2004 Houghton et al. 2004). 

Cass, C.E., Baldwin, S.A., and Young. J.D. (2001) Equilibrative nucleoside transporters mapping regions of interaction for the substrate analogue nitrobenzylthioinosine (NBMPR) using rat chimeric proteins. Biochemistry. 

The length of the microtubule cylinder may measure upto 10,000 A, but the diameter is usually 180-250 A. The polymerisation of tubulins to microtubules takes place at 37°C in presence of Mg ions, endogenous cofactors such as GTP and microtubule-associated proteins (MAPs). The depolymerisation of microtubules occurs at temperatures lower than 37°C and in presence of Ca ions. The assembly and disassembly of microtubules proceeds in a nucleated fashion and is associated with a number of cellular functions. The formation of microtubules are required to control various cell activities such as cytoplasmic movement, cell division, cell shape and substrate and vesicle transport etc. Thus, interruption of the microtubulin assembly by a chemotherapeutic agent would result in several cellular dysfunctions leading to death of the parasites. Several drugs are known to bind with tubulin and block its polymerisation into microtubules. This results in gradual disappearance of microtubules from the cells. Consequently cytoplasmic movement and transport of nutrients are disturbed. These abnormal conditions cause death of the cell [59,60]. 

More recently, our group and the joint laboratories of Baringhaus and Kramer have reported on the three-dimensional structural requirements of ASBT that will be of specific use in the development of novel substrates for this transport protein. By use of a training set of 17 chemically diverse inhibitors of ASBT, Baringhaus and colleagues (281) developed an en-antiospecific catalyst pharmacophore that mapped the molecular features essential for ASBT affinity one hydrogen bond donor, one hydrogen bond acceptor, and three hydropho-... 

In a SG/TC experiment, the spatial and temporal mapping of concentration profiles of species coming from (or being consumed in) the studied process is performed. Classical theories for linear or hemispherical diffusion that relates concentration vs. time and spatial coordinates (3) can be used to calculate kinetic parameters of chemical and electrochemical processes, as well as mass-transport coefficients. When the substrate is a large surface, linear diffusion of the substrate-generated (or consumed) species is observed, and the... 

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