Abstract
Transporters play a vital role in both the resistance mechanisms of existing drugs and effective targeting of their replacements. Melarsoprol and diamidine compounds similar to pentamidine and furamidine are primarily taken up by trypanosomes of the genus Trypanosoma brucei through the P2 aminopurine transporter. In standardized competition experiments with [(3)H]adenosine, P2 transporter inhibition constants (K(i)) have been determined for a diverse dataset of adenosine analogs, diamidines, Food and Drug Administration-approved compounds and analogs thereof, and custom-designed trypanocidal compounds. Computational biology has been employed to investigate compound structure diversity in relation to P2 transporter interaction. These explorations have led to models for inhibition predictions of known and novel compounds to obtain information about the molecular basis for P2 transporter inhibition. A common pharmacophore for P2 transporter inhibition has been identified along with other key structural characteristics. Our model provides insight into P2 transporter interactions with known compounds and contributes to strategies for the design of novel antiparasitic compounds. This approach offers a quantitative and predictive tool for molecular recognition by specific transporters without the need for structural or even primary sequence information of the transport protein.
Highlights
Trypanosoma brucei are unicellular trypanosomal parasites that cause African sleeping sickness in humans and nagana in livestock
The efficacy of many drugs is determined to a large extent by the processes that govern their uptake into the cell or into the cellular compartment that is the site of action [7, 17,18,19]. These processes obviously include transporters for water-soluble drugs but even rates of diffusion for lipophilic drugs. An example of the latter is chloroquine, which as a weak base diffuses across several membranes before it reaches the Plasmodium falciparum food vacuole where it is trapped by protonation and fatally inhibits heme polymerization [20, 21]
In silico screening of virtual libraries and predictions of substrate affinity are possible for proteins with known or computable structure (24 –26), this is not ordinarily possible for transporters as very few structures have been obtained, and the protein structures, with usually 10 –12 transmembrane domains, are highly complex and extremely difficult to crystallize, there have recently been some notable successes, mostly with prokaryotic membrane proteins [27,28,29]
Summary
Trypanosoma brucei are unicellular trypanosomal parasites that cause African sleeping sickness in humans and nagana in livestock. Final Pharmacophore Model—Aligned by the N(R1)ϭC(R2)NH(R3) structure with respect to contour regions, as described above, compounds were employed for PLS modeling. Molecular descriptors produces more linear pKi predictions, especially for compounds with high affinity for the P2 adenosine transporter (Fig. 4).
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