Department of Pharmaceutical Sciences, UCI

This is a talk/status report given on our BLUES technique for estimating fragment binding mode occupancies; it was presented at the OpenEye CUP Meeting in Santa Fe, NM, March 8, 2018. This work is in the area of structure-based drug design and we are working on modeling techniques to efficiently estimate populations of metastable ligand binding modes. The presentation is made available in PowerPoint and Keynote formats and includes movies, so the files are large.

This provides electronic supporting materials, especially input files and trajectory files, associated with our work "Is ring breaking feasible in relative binding free energy calculations?" 

Enzymes embedded into the RNA editing core complex (RECC) catalyze the U-insertion/deletion editing cascade to generate open reading frames in trypanosomal mitochondrial mRNAs. The sequential reactions of mRNA cleavage, U-addition or removal, and ligation are directed by guide RNAs (gRNAs). We combined proteomic, genetic, and functional studies with sequencing of total and complex-bound RNAs to define a protein particle responsible for the recognition of gRNAs and pre-mRNA substrates, editing intermediates, and products. This approximately 23-polypeptide tripartite assembly, termed the RNA editing substrate binding complex (RESC), also functions as the interface between mRNA editing, polyadenylation, and translation. Furthermore, we found that gRNAs represent only a subset of small mitochondrial RNAs, and yet an inexplicably high fraction of them possess 3' U-tails, which correlates with gRNA's enrichment in the RESC. Although both gRNAs and mRNAs are associated with the RESC, their metabolic fates are distinct: gRNAs are degraded in an editing-dependent process, whereas edited mRNAs undergo 3' adenylation/uridylation prior to translation. Our results demonstrate that the well-characterized editing core complex (RECC) and the RNA binding particle defined in this study (RESC) typify enzymatic and substrate binding macromolecular constituents, respectively, of the ∼40S RNA editing holoenzyme, the editosome.

The endogenous cannabinoid system is a new signaling system composed by the central (CB1) and the peripheral (CB2) receptors, and several lipid transmitters including anandamide and 2-arachidonylglycerol. This system is the target of natural cannabinoids, the psychoactive constituents of Cannabis sativa preparations (marijuana, hashish). Acute and chronic cannabis exposure has been associated with subjective feelings of pleasure and relaxation, but also to the onset of psychiatric syndromes, a decrease of the efficacy of neuroleptics and alterations in the extrapyramidal system regulation of motor activity. These actions point to a tight association of the cannabinoid system with the brain dopaminergic circuits involved in addiction, the clinical manifestation of positive symptoms of schizophrenia and Parkinson's disease. The present work discusses anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1 receptors are present in dopamine projecting brain areas. In primates and certain rat strains it is also located in dopamine cells of the A8, A9 and A10 mesencephalic cell groups, as well as in hypothalamic dopaminergic neurons controlling prolactin secretion. CB1 receptors co-localize with dopamine D1/D2 receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able to alter the synthesis and release of anandamide as well as the expression of CB1 receptors. Additionally, CB1 receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1 receptor potentiates the facilitatory role of dopamine D2 receptor agonists on movement. CB1 stimulation results in sensitization to the motor effects of indirect dopaminergic agonists. The dynamics of these changes indicate that the cannabinoid system is an activity-dependent modulator of dopaminergic transmission, an hypothesis relevant for the design of new therapeutic strategies for dopamine-related diseases such as the psychosis and Parkinson's disease.

After the first seed concept introduced in the 18th century, different disciplines have attributed different names to dual-functional molecules depending on their application, including bioconjugates, bifunctional compounds, multitargeting molecules, chimeras, hybrids, engineered compounds. However, these engineered constructs share a general structure: a first component that targets a specific cell and a second component that exerts the pharmacological activity. A stable or cleavable linker connects the two modules of a chimera. Herein, we discuss the recent advances in the rapidly expanding field of chimeric molecules leveraging chemical biology concepts. This Perspective is focused on bifunctional compounds in which one component is a lead compound or a drug. In detail, we discuss chemical features of chimeric molecules and their use for targeted delivery and for target engagement studies.