The drug efflux pump P-glycoprotein (P-gp) has been shown to promote multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. Here we synthesized and tested a series of benzophenone derivatives structurally analogous to propafenone-type inhibitors of P-gp. Some of the compounds showed ligand efficiency and lipophilic efficiency (LipE) values in the range of compounds which entered clinical trials as MDR modulators. Interestingly, although lipophilicity plays a dominant role for P-gp inhibitors, all compounds investigated showed LipE values below the threshold for promising drug candidates. Docking studies of selected analogues into a homology model of P-glycoprotein suggest that benzophenones show an interaction pattern similar to that previously identified for propafenone-type inhibitors.

Trypanosoma brucei encodes a relatively high number of genes of the equilibrative nucleoside transporter (ENT) family. We report here the cloning and in-depth characterization of one T. brucei brucei ENT member, TbNT9/AT-D. This transporter was expressed in Saccharomyces cerevisiae and displayed a uniquely high affinity for adenosine (K m ϭ 0.068 Ϯ 0.013 M), as well as broader selectivity for other purine nucleosides in the low micromolar range, but was not inhibited by nucleobases or pyrimidines. This selectivity profile is consistent with the P1 transport activity observed previously in procyclic and longslender bloodstream T. brucei, apart from the 40-fold higher affinity for adenosine than for inosine. We found that, like the previously investigated P1 activity of long/slender bloodstream trypanosomes, the 3Ј-hydroxy, 5Ј-hydroxy, N3, and N7 functional groups contribute to transporter binding. In addition, we show that the 6-position amine group of adenosine, but not the inosine 6-keto group, makes a major contribution to binding (⌬G 0 ϭ 12 kJ/mol), explaining the different K m values of the purine nucleosides. We further found that P1 activity in procyclic and long-slender trypanosomes is pharmacologically distinct, and we identified the main gene encoding this activity in procyclic cells as NT10/AT-B. The presence of multiple P1-type nucleoside transport activities in T. brucei brucei facilitates the development of nucleoside-based treatments for African trypanosomiasis and would delay the onset of uptake-related drug resistance to such therapy. We show that both TbNT9/ AT-D and NT10/AT-B transport a range of potentially therapeutic nucleoside analogs.

The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50) prediction of identified hits. Finally selected two hits were experimentally evaluated for hERG inhibition potential (pIC50) using whole cell patch clamp assay. Overall, our results demonstrate a difference of less than ±1.6 log unit between experimentally determined and predicted hERG inhibition potential (IC50) of the selected hits. This revealed predictive ability and robustness of our models and could help in correctly rank the potency order (lower μM to higher nM range) against hERG.

IntroductionBRAC, an international development organisation based in Bangladesh, uses female volunteer community health workers called Shasthya Shebika (SS), who receive small incentives to implement its home-fortification interventions at the community level. This paper examines the individual, community and BRAC work environment factors that exert an influence on the performance of SS.

γ-Aminobutyric acid (GABA) Transporters (GATs) belong to sodium and chloride dependent-transporter family and are widely expressed throughout the brain. Notably, GAT1 is accountable for sustaining 75% of the synaptic GABA concentration and entails its transport to the GABAA receptors to initiate the receptor-mediated inhibition of post-synaptic neurons. Imbalance in ion homeostasis has been associated with several neurological disorders related to the GABAergic system. However, inhibition of the GABA uptake by these transporters has been accepted as an effective approach to enhance GABAergic inhibitory neurotransmission in the treatment of seizures in epileptic and other neurological disorders. Here, we reviewed computational methodologies including molecular modeling, docking, and molecular dynamic simulations studies to underscore the structure and function of GAT1 in the GABAergic system. Additionally, various SAR and QSAR methodologies have been reviewed to probe the 3D structural features of inhibitors required to modulate GATs activity. Overall, present review provides an overview of crucial role of GAT1 in GABAergic system and its modulation to evade neurological disorders.