Transporters are proteins that span the plasma membrane and regulate the traffic of small molecules in and out of the cell. They play a particularly important role in chemical signalling between neurons in the CNS, where they act to control the concentration of neurotransmitters in the synapse. Another key role for transporters is in excluding undesirable xenobiotics from the cell, whilst allowing key molecules required for the cell life cycle to enter. The majority of transporters are targets for drug discovery.

Also important targets are auxiliary transport proteins. They in some way facilitate transport across one or more biological membranes but do not themselves participate directly in transport are included in this class. These proteins always function in conjunction with one or more established transport systems. They may provide a function connected with energy coupling to transport, play a structural role in complex formation, serve a biogenic or stability function or function in regulation.

OTAVAchemicals offers Transporter Modulators Library (525 compounds) and Auxiliary Transport Proteins Targeted Library (182 compounds). Bayesian statistics was used for design of the libraries. Templates (training sets) of ligands with known activity against main classes of transporters and auxiliary transport proteins taken from ChEMBL have been used for Bayesian modeling.

Three training sets of bioactive reference molecules were used for Transporter Modulators Library: for electrochemical transporters (SLC superfamily of solute carriers, vesicular neurotransmitter transporter family) activity cutoff was 10 nM, for primary active transporters (ATP-binding cassette, P-type ATPase, F-type and V-type ATPases, endoplasmic reticular retrotranslocon family, oxidoreduction-driven transporters) and other (transmembrane 1-electron transfer carriers, group translocator) – 100 nM. One training set was used for Auxiliary Transport Proteins Targeted Library. It included bioactive reference molecules for calcium channel auxiliary subunit alpha2delta family, fatty acid binding protein family, calcium channel auxiliary subunit gamma family, calcium channel auxiliary subunit beta family, slow voltage-gated potassium channel accessory protein family, calcium-activated potassium channel auxiliary subunit slowpoke-beta family and voltage-gated potassium channel beta-subunit family. Activity cutoff was 10 nM.

The models were developed for each training sets based on FCFP4, ECFP4, FCFP6 and ECFP6 fingerprints and molecular descriptors, such as LogP, molecular weight, number of rings, number of rotatable bonds, number of hydrogen acceptors and donors and molecular polar surface area. Limits of values of different molecular descriptors of the training set were calculated. Then values of the same descriptors for each investigated compound of OTAVAchemicals compound сollection were checked whether template limits. Compound will be active more likely if more matches (true) of descriptor values with the template limlts. All probabilities of activity are calculated rather special mathematical apparatus. Thus Bayesian model estimates how the compounds similar to the template for all the given parameters, including structural (fingerprints). Only top-scored compounds were selected.

General scheme of the approach is presented below:

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