ZHANG
LABORATORY

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Research Focus

The studies of Zhang laboratory focus on computer-aided drug discovery. We use molecular simulation and structural biology approaches to study drug related biological systems. By gaining the knowledge of the structure, dynamics and function relationship of drug targets, we develop and apply theoretical and computational methods, including structure-based and ligand-based design, in silico screening, pharmacophore modeling and QSAR analysis, to identify novel chemical reagents to modulate protein functions for the treatment of diseases.

Target mitotic kinesins for cancer treatments

Kinesins are cytoskeletal motor proteins that utilize the energy from ATP hydrolysis to perform mechanical work along MTs and mediate cellular processes such as cargo transport, spindle and chromosome movement. Mitotic kinesins are required for various aspects of mitosis, including bipolar spindle assembly, chromosome alignment, chromosome segregation and cytokinesis.  Inhibition of cell mitosis is a clinically validated strategy for cancer treatment. However, traditional anti-mitotic drugs, which target the multi-functional microtubule (MT), may cause serious side effects. Since mitotic kinesins function exclusively during mitosis, compounds specifically inhibit mitotic kinesins could affect only the proliferating cells, and thus are anticipated to be a new type of chemotherapeutic agents with better safety profiles.

Among the potential kinesin drug targets (e.g. Eg5, CENP-E, KIF3a), we are specifically interested in an unique mitotic kinesin KIFC1. Chromosomal instability (CIN) is a hallmark of many tumors and is frequently caused by extra centrosomes that transiently disrupt the normal bipolar spindle geometry needed for accurate chromosome segregation. It has been demonstrated that KIFC1 is required for the survival of cancer cells with multiple centrosomes, and more importantly, it is nonessential for normal cells. Therefore, specific inhibition of KIFC1 could be a promising strategy to selectively kill cancer cells without damaging normal healthy cells. Through HTS and structural-based drug design, we have identified small molecule KIFC1 inhibitors. One of the identified inhibitors, SR31527, binds directly to KIFC1 with an IC50 value of 6.6 µM against MT-stimulated KIFC1 ATPase activity. SR31527 prevented bipolar clustering of extra-centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell viability with IC50 values between 20 and 33 µM in TNBC cell lines MDA-MB-231, BT549 and MDA-MB-435s. Importantly, SR31527 displayed no cytotoxic effects on LL47 fibroblasts at the concentration up to 50 µM, indicating that SR31527 shows good selectivity against cancer cells. Further drug discovery efforts based on SR31527 as well as other chemical series are currently ongoing.

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Small molecule modulators of glucose transporter (GLUTs)

Cellular uptake of glucose is a fundamental process for metabolism, growth and homeostasis. Glucose transporters (GLUTs) catalyse facilitative diffusion of glucose and other monosaccharides across biomembranes. GLUTs function by alternative exposure of the substrate-binding site(s) to either side of the membrane through cycles of conformational changes of the transporter. Malfunction of GLUTs are associated with different deleterious diseases, including cancer. GLUT1 and GLUT3 are overexpressed in different types of solid tumours and thus are potential drug targets for cancer therapeutics.

Glioblastomas (GBMs) are one of the most aggressive, deadly cancers due in part to the ability of a subset of tumor cells, called brain tumor initiating cells (BTICs), to resist current treatments and cause tumor recurrence. Increased glucose uptake of BTICs is associated with elevation of the glucose transporter GLUT3. By exploring the atomic detail of GLUTs conformational changes by molecular simulation studies, we are interested in designing small molecule agents to regulate the ‘alternating access’ cycle of GLUTs for cancer treatments. Through a preliminarily structure-based virtual screening (SBVS) effort, we have identified two GLUT3 inhibitors which significantly decreased the growth of BTICs derived from multiple GBM xenografts at micromolar concentrations, but did not decrease normal human astrocyte growth. These data indicate the potential for an anti-GLUT3 therapeutic window and support the application of structure-based computational methods. In collaboration with Dr. Anita Hjelmeland at UAB, we currently conduct drug discovery studies, involving molecular modeling, ligand-based and structure-based virtual screening, computer-aided drug design, chemical synthesis and biological evaluations, to identify small molecule GLUT3-selective inhibitors for the treatment of GBM.

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Targeting frizzled receptors for Wnt/β-catenin signaling inhibitors

Wnt proteins are secreted glycoproteins that bind to the N-Untitled-2terminal extra-cellular cysteine-rich domain (CRD) of the Frizzled (Fzd) receptor family and Wnt co-receptor the low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 to activate the canonical β-catenin pathway. Activation of Wnt/β-catenin signaling has been found to be important for both initiation and progression of cancers of different tissues. Disruption of Wnt/β-catenin signal represents an opportunity for rational cancer chemoprevention and therapy.

 

We are interested in identifying small molecule inhibitors that can either directly block Wnt/Fzd interactions or interrupt/regulate Wnt signaling via binding to the transmembrane domain of Fzd. Using computational methods, we have identified several Wnt inhibitors that bound to the CRD of Fzd7 and blocked the Wnt/Fzd7 interactions. One compound, SRI-35955, showed nM potencies at the Wnt reporter assay. SRI-35955 significantly inhibited colorectal and breast cancer cell proliferation but is less cytotoxic to MCF-10A mammary epithelial cells. In collaboration with Dr. Yonghe Li, we are conducting computer-aided hit expansion and lead optimization to improve the potency and drug-like properties of SRI-35955 and other identified active compounds.

 

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Allosteric regulation of drug targets

Allosteric regulation is one of the most common and powerful means to regulate protein functions. Modulation of the allosteric sites of protein targets provides opportunities for identifying unique molecules with several therapeutic advantages over active-site targeted ligands, such as improved subtype selectivity, reduced drug resistance and the ability to selectively tune (activate or inhibit) the response of target protein. We are interested in understanding the underlying mechanism of allosteric regulation by identifying, targeting and validating novel allosteric drug binding site(s) through combined application of computational (MD simulation, CADD, cheminformatics) and experimental techniques (NMR, mutagenesis, BLI, etc.).

Other projects

We are actively involved in different computer-aided drug discovery (CADD) studies, including projects supported by NIAID service resource (for testing of anti-HIV therapeutics and topical microbicides), Antiviral Drug Discovery and Development Center , Alabama Drug Discovery Alliance as well as Southern Research Institute.

Wei Zhang

Senior Scientist, Chemistry Department

Wei Zhang, Ph.D., is a computational chemist in the Chemistry Department of Southern Research. He joined SR as a research scientist in 2007. Wei’s main research interests are to develop and utilize computational approaches to study biological systems and support drug discovery in the areas of cancer and CNS diseases. [ Read Full Bio Here ]

Sixue Zhang

Sixue Zhang

Postdoctoral Fellow

Sixue Zhang is a post-doc in the Chemistry Department of Southern Research Institute. He joined SRI in 2016. His main research area are computer-aided drug design, bioinformatics, and cheminformatics. He utilizes a wide range of computational approaches to study the drug-target interactions and is in close collaborations with other chemists and biologists.
He received his bachelor degree in Chemistry from Fudan University in Shanghai, China, in 2011. He was also trained for chemical biology techniques through his undergraduate projects. Under the supervision of Prof. Sharon Hammes-Schiffer, he received his doctorate degree in Chemistry from University of Illinois at Urbana-Champaign in 2016. His PhD research topic was the computational study of ribozyme reaction mechanisms.

Publications on PubMed:



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