Simulation-based cheminformatic analysis of organelle-targeted molecules: lysosomotropic monobasic amines

Cell-based molecular transport simulations are being developed to facilitate exploratory cheminformatic analysis of virtual libraries of small drug-like molecules. For this purpose, mathematical models of single cells are built from equations capturing the transport of small molecules across membranes. In turn, physicochemical properties of small molecules can be used as input to simulate intracellular drug distribution, through time. Here, with mathematical equations and biological parameters adjusted so as to mimic a leukocyte in the blood, simulations were performed to analyze steady state, relative accumulation of small molecules in lysosomes, mitochondria, and cytosol of this target cell, in the presence of a homogenous extracellular drug concentration. Similarly, with equations and parameters set to mimic an intestinal epithelial cell, simulations were also performed to analyze steady state, relative distribution and transcellular permeability in this non-target cell, in the presence of an apical-to-basolateral concentration gradient. With a test set of ninety-nine monobasic amines gathered from the scientific literature, simulation results helped analyze relationships between the chemical diversity of these molecules and their intracellular distributions

Selective Targeting of Tumorigenic Cancer Cell Lines by Microtubule Inhibitors

For anticancer drug therapy, it is critical to kill those cells with highest tumorigenic potential, even when they comprise a relatively small fraction of the overall tumor cell population. We have used the established NCI/DTP 60 cell line growth inhibition assay as a platform for exploring the relationship between chemical structure and growth inhibition in both tumorigenic and non-tumorigenic cancer cell lines. Using experimental measurements of “take rate” in ectopic implants as a proxy for tumorigenic potential, we identified eight chemical agents that appear to strongly and selectively inhibit the growth of the most tumorigenic cell lines. Biochemical assay data and structure-activity relationships indicate that these compounds act by inhibiting tubulin polymerization. Yet, their activity against tumorigenic cell lines is more selective than that of the other microtubule inhibitors in clinical use. Biochemical differences in the tubulin subunits that make up microtubules, or differences in the function of microtubules in mitotic spindle assembly or cell division may be associated with the selectivity of these compounds

Down-Regulation of Myogenin Can Reverse Terminal Muscle Cell Differentiation

Certain higher vertebrates developed the ability to reverse muscle cell differentiation (dedifferentiation) as an additional mechanism to regenerate muscle. Mammals, on the other hand, show limited ability to reverse muscle cell differentiation. Myogenic Regulatory Factors (MRFs), MyoD, myogenin, Myf5 and Myf6 are basic-helix-loop-helix (bHLH) transcription factors essential towards the regulation of myogenesis

Chemical biology and chemical genetics - Preface

11sciescopu

Targeting hyperproliferative disorders with cyclin dependent kinase inhibitors

Deregulated cell proliferation is associated with a variety of diseases including dysplasias and metaplasias of different tissues, psoriasis, atherosclerosis, restenosis after angioplastic surgery, and cancer [1-3]. Until recently, treatments for hyperproliferative disorders have revolved around chemical agents that kill actively dividing cells [4]. These agents include drugs that block DNA synthesis, such as DNA alkylators, topoisomerase, polymerase and nucleotide biosynthesis inhibitors. In addition, microtubule depolymerising and stabilising compounds have had widespread use as agents that interfere with Spindle function essential for chromosome segregation and the process of cell division. Over the last seven years, understanding the mechanism;regulating entry and exit, from the cell cycle has led to the identification of signal transduction, transcriptional and cell cycle regulatory pathways orchestrating cell proliferation. Abnormalities in these regulatory mechanisms have been implicated in a variety of hyperproliferative disorders, prompting the development of cyclin-dependent kinase(CDK) inhibitors as therapeutic agents [5-9]. Unlike drugs that are meant to kill actively dividing cells, CDK inhibitors can be used to re-establish order in the biochemical mechanisms governing a cell's decision to grow and divide - a departure from the traditional chemotherapeutic approach to the treatment of hyperproliferative disorders.1134sciescopu

Inositol phospholipid pathway inhibitors and regulators

In health and disease. physiological homeostasis depends on the ability: of cells to respond to the environment and other cells. Communications between cells are mediated by a variety of chemical signals such as hormones, growth factors, neurotransmitters or electric signals [1]. Although chemical signalling occurs by a. number of different mechanisms, signalling molecules can be classified into two general types according to their ability to permeate the plasma membrane. While hydrophobic hormones easily penetrate the lipid bilayer and directly act on intracellular or nuclear receptors, cell impermeant, hpdrophilic molecules bind to cell surface receptors embedded ill the lipid bilayer and thus generate second messengers that transmit the extracellular signal to the intracellular compartment. In many different cell types, this latter process, referred to as trans-membrane signalling or signal transduction, is mediated by protein phosphorylation cascades, ion fluxes, as well as changes in the levels of phospholipid breakdown products including diacylglycerol and myo-inositol containing second messengers [2]. Misregulation of inositol signalling pathways has been implicated in a variety of diseases, including hypertension, diabetes and neuronal disorders, prompting the development of pharmacological agents that re-establish normal inositol signalling. Here, we review the patent literature surrounding small molecule inositol derivatives and discuss the challenges that remain before therapeutic applications become practical.1114sciescopu

Dedifferentiation? What's next?

Not so fast! Several things need to be considered before we conclude that Chen et al. have a dedifferentiating agent on their hands. The verification of small molecules as tissue- or cell-type dedifferentiating agents will require greatly sophisticated techniques and the identification of the direct molecular targets of said small molecules. By knowing what pitfalls to avoid, intelligent small-molecule design and testing may proceed more expediently.118sciescopu

Development of novel cell-permeable DNA sensitive dyes using combinatorial synthesis and cell-based screening

A novel cell-permeable DNA fluorescence sensor was developed based on combinatorially-created styryl dyes and cell-based localization screening.1167sciescopu

Chemoinformatic analysis of a supertargeted combinatorial library of styryl molecules

Styryl dyes are fluorescent, lipophilic cations that have been used as specific labeling probes of mitochondria in living cells. For specific applications such as epifluorescence microscopy or flow cytometry, it is often desirable to synthesize fluorescent derivatives with optimized excitation, emission, and localization properties. Here, we present a chemoinformatic strategy suitable for multiparameter analysis of a combinatorial library of styryl molecules supertargeted to mitochondria. The strategy is based on a simple additive model relating the spectral and subcellular localization characteristics of styryl compounds to the two chemical building blocks that are used to synthesize the molecules. Using a cross-validation approach, the additive model predicts with a high degree of confidence the subcellular localization and spectral properties of the styryl product, from numerical scores that are independently associated with the individual building blocks of the molecule. The fit of the data indicates that more complex, nonadditive interactions between the two building blocks play a minor role in determining the molecule's optical or biological properties. Moreover, the observed additive relationship allows mechanistic inferences to be made regarding the structure-property relationship observed for this particular class of molecules. It points to testable, mechanistic hypotheses about bow chemical structure, fluorescence, and localization properties are related.1127sciescopu