West Center Research Highlights
The mission of the West Center is to contribute to human knowledge by applying cutting edge computational approaches to current challenges in chemical and biological systems and to develop new computational tools and methods to model and predict chemical and biological properties.
We include several highlights of current projects within the West Center. Each of these projects, enabled by resources within the West Center, has recently led to publications in top peer-reviewed journals. The West Center research involves a large diversity of projects, below we select a few examples which emphasize our diverse contributions ranging from drug design to creating smart surfaces for enhanced properties. We end with the training and teaching which is central to the goals of the West Center.
Drug Design Projects
Novel targeting of the Epstein-Barr virus (EPV). [Gianti, E., Messick, T.E., Lieberman, P.M. Zauhar R J.; J Comput Aided Mol Des (2016) 30: 285. DOI:10.1007/s10822-016-9899-y] EPV, is a member of the herpes virus family and one of the most common human viruses. EBV spreads most commonly through bodily fluids, primarily saliva and can cause infectious mononucleosis and other illnesses. The research cited reports a novel drug target for EPV, shown in the figure below.
Novel therapeutics for type 2 diabetes. [Structural Modeling and in Silico Screening of Potential Small-Molecule Allosteric Agonists of a Glucagon-like Peptide 1 Receptor; Tejashree Redij, Rajan Chaudhari, Zhiyu Li, Xianxin Hua, and Zhijun Li; ACS Omega 2019 4(1), 961-970 DOI:10.1021/acsomega.8b03052]. The glucagon-like peptide-1 receptor (GLP-1R) is a receptor protein found on beta cells of the pancreas. It is involved in the control of blood sugar levels by enhancing insulin secretion and is a target for the treatment of type 2 diabetes. GLP-1R agonist-based therapies represent an effective approach that results in several GLP-1 analog drugs. However, the development of nonpeptidic agonist drugs targeting GLP-1R remains unsuccessful. A promising strategy aims to develop orally bioavailable, small molecule positive allosteric modulators (PAMs) of GLP1-1R. We have designed a novel compound (S-1) with the smallest molecule weight (239) among known GLP-1R PAMs was confirmed as a GLP-1R PAM as it synergistically with GLP-1 stimulates insulin secretion. When combined with VIPR peptide agonist, S-1 showed no non-specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cells used for in vitro activity studies. The figure below shows the computational modeling and experimental validation of an allosteric modulator of GLP1R.
Ion Channel Structure and Dynamics. [Hien Nguyen, T., C. Moore, C., B. Moore, P., & Liu, Z. (2018). Molecular dynamics study of homo-oligomeric ion channels: Structures of the surrounding lipids and dynamics of water movement. AIMS Biophysics, 5(1), 50–76. DOI:10.3934/biophy.2018.1.50] Two homo-oligomeric α-helices peptides which are known to form ion channels were studied. These findings can benefit various research areas such as the rational design of novel therapeutics, in which the drug interacts with membranes and transmembrane proteins to enhance the efficacy or reduce off-target effects. Below is a figure of the structures formed from different numbers of homo-oligomers.
Surface enhancement by CORALs. [Davydovich, O., Chu, E., Friar, Z., Smilgies, D.-M., Moore, P., & Sidorenko, A. (2018). Coordinated Responsive Arrays of Surface-Linked Polymer Islands—CORALs. ACS Applied Materials & Interfaces, 10(8), 7459–7468. DOI:10.1021/acsami.7b18305] This study targets a responsive system capable of revealing or covering the substrate surface in response to environmental changes in a reversible way. The figure below shows computational and experimental validation of switchable surface and a picture of a live biological coral with the same morphology.
Functional Aromatic Foldamer Structure and Mechanism. [Liu, Z.; Hu, X.; Abramyan, A. M.; Meszaros, A.; Csekei, M.; Kotschy, A.; Huc, I.; Pophristic, V., Computational Prediction and Rationalization, and Experimental Validation of Handedness Induction in Helical Aromatic Oligoamide Foldamers. Chemistry A European Journal 2017, 23 (15), 3605-3615.] Aromatic foldamers are a novel class of abiotic oligomer which folds into stable secondary structures in solution. The interest in the design, synthesis, and application of aromatic foldamer had grown exponentially in the past decades. We developed a computational approach that enables accurate prediction of structure, mechanism and solution dynamics of aromatic foldamers. Figures below illustrate the free energy pathway for folding/unfolding of an aromatic foldamer (right), and handedness induction by terminal biasing group (left), all predicted computationally and validated by experiment. The middle figure illustrates the sequence-structure relation and the idea of the computational design of different structural features (ex. helix diameter).
Broad Reach of the West Center
The West Center does much more than provide computational resources to investigators, of which we currently have 7 PI’s (Dr. Moore, Dr. Liu, Dr. Li, Dr. Pophristic, Dr. Bruist, Dr. Khashan, and Dr. Zauhar), of which we have highlighted only a small subset of theirs research. Beyond the research and central to the West Center’s mission is to “assist scientists in acquiring the expertise and skills related to computational uses in chemistry and biology”. To that end, we continue to be involved in teaching and training at all levels. For example, there have been many high-school students, undergraduate students, graduate students, postdoctoral fellows, and visiting scientists that been part of the West Center through the years. West Center alumni have gone on to have very successful careers for themselves of all types, from academia (e.g chair of chemistry departments) to industry (e.g. senior VP of product development) to research centers (e.g. Head data scientist at the Center for Applied Genomics at the Childers Hospital of Philadelphia).
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