Ligands

The emergence of bacterial multidrug resistance is an increasing problem in treatment of infectious diseases. An important cause for the multidrug resistance of bacteria is the expression of multidrug efflux transporters. The multidrug and toxic compound extrusion (MATE) transporters are most recently recognized as unique efflux system for extrusion of antimicrobials and therapeutic drugs due to energy stored in either Na(+) or H(+) electrochemical gradient.

Bile acids are detergent molecules derived from cholesterol in the liver that are important for the metabolism and absorption of lipids in the intestine. Bile acids are also steroid hormones activating specific nuclear receptors and G protein-coupled receptors. Conjugated bile acids are cytoprotective and anticarcinogenic. Bile acid synthesis and bile flow decreases markedly during aging.

Lipocalins are a family of proteins characterized by a conserved eight-stranded ?-barrel structure with a ligand-binding pocket. They perform a wide range of biological functions and this functional multiplicity must relate to the lipid partner involved. Apolipoprotein D (ApoD) and its insect homologues, Lazarillo (Laz) and neural Lazarillo (NLaz), share common ancestral functions like longevity, stress resistance and lipid metabolism regulation, coexisting with very specialized functions, like courtship behavior.

Certain endogenous steroids are modulators of GABAA receptors. Tetrahydroprogesterone (THP, 5 alpha-pregnan-3 alpha-ol-20-one) and tetrahydrodeoxy-corticosterone (THDOC, 5 alpha-pregnane-3 alpha, 21-diol-20-one) behave as allosteric agonists of GABAA receptors whereas pregnenolone sulphate acts as an antagonist. THP and THDOC modulate ligand binding to GABAA receptors like barbiturates; they potentiate binding of the GABAA receptor agonist muscimol and the benzodiazepine flunitrazepam and they allosterically inhibit binding of the convulsant t-butylbicyclophosphorothionate.

Gamma hydroxybutyric acid (GHB), an endogenous constituent of the mammalian brain, acts as i) a neurotransmitter or neuromodulator, ii) a medicine used for the treatment of narcolepsy and alcoholism, and iii) a drug illicitly used for its psychotropic effects. GHB is thought to act as a specific GHB receptor agonist as well as a weak gamma-aminobutyric acid type B (GABA(B)) receptor agonist. Here, I review the in vivo and in vitro pharmacological properties of GHB and its interaction with GHB and GABA(B) receptors.

Glutathione S-transferase of the malarial parasite Plasmodium falciparum (PfGST) represents a novel class of GST isoenzymes. Since the architecture of the PfGST substrate binding site differs significantly from its human counterparts and there is only this one isoenzyme present in the parasite, PfGST is considered a highly attractive target for antimalarial drug development. Here we report the mechanistic, kinetic, and structural characterization of PfGST as well as its interaction with different ligands.

The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P.

BACKGROUND AND PURPOSE: Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH: A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking.

The Pd-catalyzed TBHP-mediated Wacker-type oxidation of internal alkenes is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)quinoline (Quinox) as ligand and TBHP(aq) as oxidant to deliver single ketone constitutional isomer products in a predictable fashion from electronically biased olefins. This methodology is showcased through its application on an advanced intermediate in the total synthesis of the antimalarial drug artemisinin.

Artemisinin (ART) and its derivatives artesunate (AS), dihydroartemisinin (DHA) are a group of drugs containing a sesquiterpene lactone used to treat malaria. Previously, AS was shown to not have antibacterial activity but to significantly increase the antibacterial activities of ?-lactam antibiotics against E. coli. Herein, molecular docking experiments showed that ART, AS and DHA could dock into AcrB very well, especially DHA and AS; both DHA and AS had the same docking pose.