112 research outputs found
Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery
Gαq-containing G proteins regulate B cell selection and survival and are required to prevent B cellâdependent autoimmunity
Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the Gαq subunit of trimeric G proteins (Gnaqâ/â mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaqâ/â B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaqâ/â chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaqâ/â B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity
Risk and protective factors for structural brain ageing in the eighth decade of life
Individuals differ markedly in brain structure, and in how this structure degenerates during ageing. In a large sample of human participants (baseline nâ=â731 at age 73 years; follow-up nâ=â488 at age 76 years), we estimated the magnitude of mean change and variability in changes in MRI measures of brain macrostructure (grey matter, white matter, and white matter hyperintensity volumes) and microstructure (fractional anisotropy and mean diffusivity from diffusion tensor MRI). All indices showed significant average change with age, with considerable heterogeneity in those changes. We then tested eleven socioeconomic, physical, health, cognitive, allostatic (inflammatory and metabolic), and genetic variables for their value in predicting these differences in changes. Many of these variables were significantly correlated with baseline brain structure, but few could account for significant portions of the heterogeneity in subsequent brain change. Physical fitness was an exception, being correlated both with brain level and changes. The results suggest that only a subset of correlates of brain structure are also predictive of differences in brain ageing
Technically Extended MultiParameter Optimization (TEMPO): An Advanced Robust Scoring Scheme To Calculate Central Nervous System Druggability and Monitor Lead Optimization
At the discovery stage, it is important
to understand the drug
design concepts for a CNS drug compared to those for a non-CNS drug.
Previously, we published on ideal CNS drug property space and defined
in detail the physicochemical property distribution of CNS versus
non-CNS oral drugs, the application of radar charting (a graphical
representation of multiple physicochemical properties used during
CNS lead optimization), and a recursive partition classification tree
to differentiate between CNS- and non-CNS drugs. The objective of
the present study was to further understand the differentiation of
physicochemical properties between CNS and non-CNS oral drugs by the
development and application of a new CNS scoring scheme: Technically
Extended MultiParameter Optimization (TEMPO). In this multiparameter
method, we identified eight key physicochemical properties critical
for accurately assessing CNS druggability: (1) number of basic amines,
(2) carbonâheteroatom (non-carbon, non-hydrogen) ratio, (3)
number of aromatic rings, (4) number of chains, (5) number of rotatable
bonds, (6) number of H-acceptors, (7) computed octanol/water partition
coefficient (AlogP), and (8) number of nonconjugated C atoms in nonaromatic
rings. Significant features of the CNS-TEMPO penalty score are the
extension of the multiparameter approach to generate an accurate weight
factor for each physicochemical property, the use of limits on both
sides of the computed property space range during the penalty calculation,
and the classification of CNS and non-CNS drug scores. CNS-TEMPO significantly
outperformed CNS-MPO and the SchroÌdinger QikProp CNS parameter
(QP_CNS) in evaluating CNS drugs and has been extensively applied
in support of CNS lead optimization programs
Overexpression of complement inhibitor crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis
Synthesis and Mixed Lineage Kinase Activity of Pyrrolocarbazole and Isoindolone Analogs of (+)K-252a
A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: StructureâActivity Relationships for a Series of 9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1- a
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