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Unilever-RCEES Cooperative Project on Predictive Screening Tools

1. Title


Molecular Simulation Investigation on MIE of Typical Hormone Receptor-Mediated Effect: Calculation and Verification


2. Background Profile


According to the concept of Toxicity Testing in the 21st Century, biomolecules maintain related cell function and signaling pathways through interactions with small molecular substances. Exogenous chemicals are able to interact with endogenous biomolecules to disturb related downstream signaling cascade. The toxicity may be observed when such perturbation of intracellular toxicity pathway becomes excessive and consequently propagate into special adverse impacts on the cellular functions finally even on individual level via programmed regulations. Obviously, the initial interactions between chemicals and biomolecules are one of the key steps of any toxicity pathways. Every toxicity pathway starts with a molecular initiating event (MIE). The future of toxicity testing demands a methodological shift from whole-animal-based testing to cell-based in vitro testing and computational toxicology, such that it is essential to explore mechanisms underlying both different MIEs and linkage between MIEs and specific adverse outcomes. However, there are diverse mechanisms of action (MOA) dominating the chemical related processes of MIEs. The electrophilic potential of the chemical metabolite and its subsequent reaction between protein or DNA can result in the adduct formation, while hydrogen bound establishment, hydrophobic contact and steric hindrance may determine the MIE involving receptor binding. Different computational methods are needed to develop for elucidating the corresponding MOAs for specific MIEs. Considering the key role of hormone receptors (HR) in endocrine disrupting effects of chemicals and prevailing metabolic syndrome, the effective evaluation methodology of ligand-receptor interaction and its subsequent effectin silico is proposed as first-priority research interest.


Present virtual screening methods normally adopt typical cavity/ligand structure characteristics query strategy which is quite insufficient to predict all possible binding modes. Frequently, a higher virtual screening score does not necessarily correspond to higher biological activity because of false negatives from the docking procedures. Beside, such prediction in silico lead to not only unacceptable lower screening hit rates but also serious deficiencies in distinguishing the receptor-mediated effects (out comes such as agonism and antagonism) and evaluating the environment factor-dependent nature of the ligand-receptor interaction, dimerization as well as co-regulator recruitment. Moreover, neither the molecular mechanisms of adaption and adversity for such interaction nor the time evolution profile of the MIE can be clarified. Molecular dynamics (MD) approaches provide a feasible way to tackle the issue since MD simulations can obtain information that is not accessible from static structure. Moreover, estrogen receptor (ER) and thyroid hormone receptor (TR), belonging to two types of nuclear receptors, are selected as receptor models for the MD study. Specifically, ERs belong to Type I receptors which are largely located in the cytosol of cells in complex with heat shock proteins (HSP) in the absence of hormones. Estrogen binding to an ER triggers a number of events starting with dissociation of HSP, translocation into the cell nucleus, dimerization with another ER, and subsequent binding of the homo-dimer to specific sequences of DNA known as estrogen response elements (ERE). Disruption of ER pathway has been reported to be related to many diseases such as cancer and obesity. Different from ERs, TRs belong to Type II receptors locating in the cell nucleus and hetero-dimerizing with retinoid X receptor (RXR). In the absence of hormones, the dimer binds to hormone response elements of the target gene together with co-repressor proteins. Binding of thyroid hormones leads to a conformational change in TR which then releases co-repressors and recruits co-activator proteins that are responsible for the transcription of target genes. The most important functions of TRs are their regulation of metabolism and the development of organisms. Thus, interference directly on TRs pathway would also result in serious effects on the human health.