ReviewIn silico strategies for modeling membrane transporter function
Section snippets
Comparative modeling
The primary amino acid sequences of many transporters are known and solution of their secondary structures is facilitated by bioinformatics tools, such as hydropathy plotting, and, preferably, by a combination of experimental verification methods, such as N-glycosylation analysis or epitope insertion scanning [3, 4]. Although only a few transporter proteins have been analyzed by X-ray crystallography and afforded high-resolution 3D information, new structures are emerging at a steady rate,
Ligand-based methods
In silico approaches based on molecular level transporter models could be used to predict ligand- and inhibitor-binding modes, thus representing a useful tool in the discovery of novel transporter substrates. Although comparative models can be generated successfully for membrane proteins with seven or 12 TMDs, this approach is not yet feasible for proteins without a suitable TMD template. In these cases, techniques that do not require knowledge of transporter structure can be applied, such as
Combination in silico approaches
In silico methods represent one of numerous useful tools to study the transport mechanism and substrate affinity requirements of membrane transporters. It efficiently fills the gap between our knowledge of atomic level transporter structural mechanisms and in vitro transporter properties derived by biochemical experiments. This type of hybrid approach will eventually lead to the discovery of safer and more efficient drugs by targeting transporters or, in the case of efflux pumps, avoiding them
Future perspectives
Clearly, the future of transporter modeling will lie in the realm of combination in silico approaches. The grouping of QSAR and homology modeling techniques has been pioneered in the receptor pharmacology area and could now be applied to transporter families. Furthermore, the emergence of expression systems and HTS methods has enabled the collection of functional data on many transporter homologues and orthologues. The era of modeling individual transporters will now give way to comparative
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