Computational Docking Technique for Drug Discovery: A Review

Computational and experimental techniques are two complimentary approaches that have important roles in drug discovery and development. Earlier time and cost of bringing a new drug in market bears a question as it takes seven to twelve years and $ 1.2 billion are often cited. Furthermore, five out of forty thousand compounds tested in animals reach human testing and only one of five compounds reaching clinical studies is approved. This accounts for a large input in terms of time, money and human and other resources. Therefore, new approaches are needed to facilitate, expedite and streamline drug discovery and development, save time, money and resources. Among many computational tools, molecular docking is one of the important means that can be used in drug discovery. It provides the information regarding the binding affinities between small molecules (ligands) and macromolecular receptor targets (proteins). Various approaches, methodology are cited in various literatures for describing the cost, time effect with success of drug discovery task. In this review, introduction of the available molecular docking methods, with simple methodology of docking and examples of drug design and discovery through computational docking methods is discussed and emphasis is made on various examples of sampling algorithms, scoring functions with their relevant characterstics with summary on type of ligand binding with receptors.

PEN Receptor GPR83 in Anxiety-Like Behaviors: Differential Regulation in Global vs Amygdalar Knockdown

Anxiety disorders are prevalent across the United States and result in a large personal and societal burden. Currently, numerous therapeutic and pharmaceutical treatment options exist. However, drugs to classical receptor targets have shown limited efficacy and often come with unpleasant side effects, highlighting the need to identify novel targets involved in the etiology and treatment of anxiety disorders. GPR83, a recently deorphanized receptor activated by the abundant neuropeptide PEN, has also been identified as a glucocorticoid regulated receptor (and named GIR) suggesting that this receptor may be involved in stress-responses that underlie anxiety. Consistent with this, GPR83 null mice have been found to be resistant to stress-induced anxiety. However, studies examining the role of GPR83 within specific brain regions or potential sex differences have been lacking. In this study, we investigate anxiety-related behaviors in male and female mice with global knockout and following local GPR83 knockdown in female mice. We find that a global knockdown of GPR83 has minimal impact on anxiety-like behaviors in female mice and a decrease in anxiety-related behaviors in male mice. In contrast, a local GPR83 knockdown in the basolateral amygdala leads to more anxiety-related behaviors in female mice. Local GPR83 knockdown in the central amygdala or nucleus accumbens (NAc) showed no significant effect on anxiety-related behaviors. Finally, dexamethasone administration leads to a significant decrease in receptor expression in the amygdala and NAc of female mice. Together, our studies uncover a significant, but divergent role for GPR83 in different brain regions in the regulation of anxiety-related behaviors, which is furthermore dependent on sex.

Classification of the mechanisms by which cardiotoxic plant poisons exert their effects

Episodes of poisoning due to plant-based toxins are an unusual presentation to the emergency department. Plant poisons may be ingested if the source plant is misidentified as benign (eg, Lily of the Valley being mistaken for wild garlic and water hemlock being mistaken for wild celery), or taken as part of a complementary medicine regime or otherwise for psychotropic effect. Numerous plant poisons demonstrate cardiotoxic effects resulting from action against cardiac myocyte ion channels, or other cardiac receptor targets. These mechanisms will produce stereotyped symptoms and including electrocardiogram (ECG) changes dependent on which ion channels or receptors are targeted. These mechanisms are stereotyped and may be grouped by toxidromic effect. This article proposes a novel classification of cardiotoxic plant poisons based on these actions. Given that these mechanisms mirror the Vaughan Williams classification used to categorise therapeutic antiarrhythmic agents, it is felt that this will serve as a mnemonic and diagnostic aid in clinical situations of cardiotoxic plant ingestion.

Cannabinoid Modulation of Dopamine Release During Motivation, Periodic Reinforcement, Exploratory Behavior, Habit Formation, and Attention

Motivational and attentional processes energize action sequences to facilitate evolutionary competition and promote behavioral fitness. Decades of neuropharmacology, electrophysiology and electrochemistry research indicate that the mesocorticolimbic DA pathway modulates both motivation and attention. More recently, it was realized that mesocorticolimbic DA function is tightly regulated by the brain’s endocannabinoid system and greatly influenced by exogenous cannabinoids—which have been harnessed by humanity for medicinal, ritualistic, and recreational uses for 12,000 years. Exogenous cannabinoids, like the primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol, produce their effects by acting at binding sites for naturally occurring endocannabinoids. The brain’s endocannabinoid system consists of two G-protein coupled receptors, endogenous lipid ligands for these receptor targets, and several synthetic and metabolic enzymes involved in their production and degradation. Emerging evidence indicates that the endocannabinoid 2-arachidonoylglycerol is necessary to observe concurrent increases in DA release and motivated behavior. And the historical pharmacology literature indicates a role for cannabinoid signaling in both motivational and attentional processes. While both types of behaviors have been scrutinized under manipulation by either DA or cannabinoid agents, there is considerably less insight into prospective interactions between these two important signaling systems. This review attempts to summate the relevance of cannabinoid modulation of DA release during operant tasks designed to investigate either motivational or attentional control of behavior. We first describe how cannabinoids influence DA release and goal-directed action under a variety of reinforcement contingencies. Then we consider the role that endocannabinoids might play in switching an animal’s motivation from a goal-directed action to the search for an alternative outcome, in addition to the formation of long-term habits. Finally, dissociable features of attentional behavior using both the 5-choice serial reaction time task and the attentional set-shifting task are discussed along with their distinct influences by DA and cannabinoids. We end with discussing potential targets for further research regarding DA-cannabinoid interactions within key substrates involved in motivation and attention.

Sensitive and quantitative detection of MHC-I displayed neoepitopes using a semi-automated workflow and TOMAHAQ mass spectrometry

Advances in several key technologies, including MHC peptidomics, has helped fuel our understanding of basic immune regulatory mechanisms and identify T cell receptor targets for the development of immunotherapeutics. Isolating and accurately quantifying MHC-bound peptides from cells and tissues enables characterization of dynamic changes in the ligandome due to cellular perturbations. This multi-step analytical process remains challenging, and throughput and reproducibility are paramount for rapidly characterizing multiple conditions in parallel. Here, we describe a robust and quantitative method whereby peptides derived from MHC-I complexes from a variety of cell lines, including challenging adherent lines, can be enriched in a semi-automated fashion on reusable, dry-storage, customized antibody cartridges. TOMAHAQ, a targeted mass spectrometry technique that combines sample multiplexing and high sensitivity, was employed to characterize neoepitopes displayed on MHC-I by tumor cells and to quantitatively assess the influence of neoantigen expression and induced degradation on neoepitope presentation.

Advances in Knowledge of Androgens: How Intentional and Accidental Neurosteroid Changes Inform Us of Their Action and Role

Purpose of Review Here, we summarize current knowledge of androgens’ action gained over the recent years. Recent Findings Neurosteroids are produced in the brain and peripheral nerves, independent of endocrine glands have been investigated for how they are regulated, and have actions via non-steroid receptor targets to mediate social, affective, and cognitive behavior and to protect the brain. Androgens’ organizing actions in the peri-natal period have effects throughout the lifetime that may be recapitulated later in life during critical periods and at times of challenge. Developmental changes in androgens occur during mid-childhood, adrenarche, puberty, adolescence, young adulthood, middle age, and andropause. Changes in androgens with a 5α-reductase inhibitor, such as finasteride, result in disruptions in organizational and activational functions of androgens that can be unremitting. Summary Normal developmental or perturbation in androgens through other means can cause changes in androgen-sensitive phenotypes throughout the lifespan, in part through actions of neurosteroids.

Propitious Profile of Peppery Piperine

Background: Piperine is a key bioactive alkaloid found in plants of piperaceae family. The compound possesses various medicinal and pharmacological activities (cholesterol lowering, anti cancer, alzheimer’s disease etc). Owing to its various target receptors (TRPV1, P-gp, CYP3A4 etc.) and several mechanisms, piperine has been studied as bio-enhancer for other drugs and its role has been evidenced in literature. When administered with other drugs, it increases absorption of other drugs thereby reducing the dose and dose related toxic potential. There are various mechanisms of piperine as a bio-enhancer and the common ones are i) prevention of efflux of drug molecules out of the cells; ii) decreased metabolism of drugs thereby prolonging half-life of drugs resulting in reduced urinary excretion. The detailed mechanism indicating bio-enhancing role of piperine along with various target receptors have not been comprehensively summarised till date. Methods: Literature related to the molecular, enzymatic and receptor targets of piperine were studied and database was collected using various search engines such as j-gate, google scholar, scihub, pubmed, sciencedirect etc. The literature related to therapeutic activities of piperine and its bio-enhancer role for other drugs has been thoroughly studied and compiled in brief. Results: A detailed summary of piperine targets along with related mechanisms has been stated. A brief therapeutic profile of piperine alone has been produced with supporting literature. Piperine role as a potential bio-enhancer for other drugs has been summarized. Conclusion: Piperine is fascinating molecule of natural origin with several modes of its action, not only possess its own therapeutic activity but also enhances the therapeutic efficacy of other synthetic and natural drug molecules. Combination dosage forms of various API incorporating piperine as a bio-enhancer can be potential area of thrust for upcoming drug design and development.