Xie received his B.S. degree in Pharmacy from the Second Military Medical University in Shanghai, China in 1982, his Ph.D. in Medicinal Chemistry from the School of Pharmacy, University of Connecticut in 1993, and followed by a Biophysics Post-doctoral training at M.I.T Francis Bitter National Magnet Laboratory. He also received an Executive MBA degree in 2003. He has specific training and expertise in medicinal/computational chemistry, computational biology and biophysics with track record of publications.
Xie is currently a tenured full Professor of Pharmaceutical Sciences/Drug Discovery Institute and Computational Biology at UPitt. I am also a faculty of joint Carnegie Mellon University/University of Pittsburgh (CMU/Pitt) Computational Biology Ph.D. Program. As PI, I have active NIH funded projects on: 1) GPCR CB2 membrane protein structure-based design using integrated approaches of structural biophysics, computational chemical genomics virtual screening/bioassay validation and medicinal chemistry, and 2) small molecule chemical probe design for hematopoietic stem cells expansion. As Founding Director of Computational Chemical Genomics Screening Center at UPitt, he currently serve as co-PI and core Director on two active NIH funded center grants (PCMLD NIH P50 and UP-CDC NCI/SAIC), and also served as co-PI on NIH PMLSC grant. Before he joined Pitt, he was a faculty of Medicinal Chemistry and a founding Director of Pharmacoinformatics Research Center in the College of Pharmacy at University of Houston Texas. He held several joint faculty positions at the Institute for Molecular Design (MDL), Texas Learning Computing Center (TLCC), the Keck Center for Computational & Structural Biology, served as an Advisory Committee Member for the NIH Pharmacoinformatics Training Program at Houston Gulf Coast Consortium (GCC), and was a Director of the Chemistry Coordinating Unit for GCC-Chemical Genomics Screening Center. Prior to UH, Dr. Xie was a Director of the IMS NMR Lab and a joint faculty member of the School of Pharmacy at the University of Connecticut for over 10 years. Dr. Xie is a regular member of the NIH BPNS Study Section Review Panel, an oversea expert reviewer for the Chinese Natural Science Foundation Review Panel, and ad hoc expert reviewer of the MCMB grant for MRC United Kingdom. He is also an invited guest editor for AAPS Journal, and an editorial board of American Journal of Molecular Biology. He was invited as an International Assessment Panelist for Fudan University.
His lab has developed and published over 100 peer-reviewed articles, book chapters, patents, meeting abstracts, including CB ligand design and QSAR pharmacophore modeling, GPCR CB2 receptor modeling, biochemical/biophysics studies, and new CB2 ligand discovery. His group also published many computational chemistry algorithms and cheminformatics tools, including LiCABEDS (Machine learning algorithm based novel GPCR ligand affinity and specificity prediction), CLAP (3D chemistry-space matrix based compound library acquisition profiling algorithm), FastMolPol (fast approaches for molecular polarizability calculations), ga-QSAR (genetic algorithm-optimized QSPR models for bioavailability, protein binding, and urinary excretion), LigFrag-RPM (Residue Preference Mapping of PDB Ligand Fragments), Fragment-based QSAR algorithm, as well as the web molecular information database and tools: CBID (www.CBLigand.org), HTDocking, TargetHunter and BBB-predictor (www.cbligand.org/xielab/technology.php).
As a Professor of Pharmaceutical Sciences/Drug Discovery Institute, Xie and his team have acquired expertise and know-how technologies/experience in drug design and discovery, and also established a research platform with the integrated 3D pharmacophore database search, in silico design and in vitro bioassay validation as well as medicinal chemistry modification approaches. The PI Xie and his team in collaboration with MD clinicians (David, Roodman and Tao Cheng, etc) have discovered/patented new chemical agents by uncover of new signaling pathways targeting multiple mye loma (MM). These were based on therapeutic hypotheses that the selective CB2 inverse agonists or p62zz inhibitors represent new drug target and novel chemical agents with therapeutic potential for MM treatment:
• CB2 chemical agents for MM intervention: (Xie, et al, patents: WO 2009058377 and USSN 61/576,041). We first discovered that CB2 receptor is highly expressed in MM cell lines, and also first to discover novel CB2 ligands potential for MM. A series of selective CB2 inverse agonists with novel chemical scaffolds were synthesized and top 3 compounds showed excellent CB2 binding affinity (< 100 nM) and effective anti-MM activity. All these compounds exhibit good drug-like properties with no or minor toxicity to normal cells.
• P62zz inhibitors potential for MM treatment: (Xie, et al, patent: USSN 61/521,287). We are also the first lab discovered P62zz chemical inhibitors. We have proved that the ZZ domain of p62 is responsible for increased MM cell growth and osteoclast (OCL) formation mediated by NF-KB and p38 MAPK signaling. A series of novel p62-ZZ compounds were discovered/synthesized. Top 2 compounds (HCl salt) demonstrated 2 µM inhibition activities to MM cells growth without toxicity to regular stromal cells. These compounds show good drug-like properties. Lead chemistry modifications are underway to optimize the inhibitory activity.
We are seeking partnership/collaboration to accelerate the new MM drug discovery.
As a Founding Director, CCGS center has developed and published several computational algorithms and cheminformatics tools, including structure-diverse and target-focused libraries for virtual screening, GPU-accelerated diversity oriented combichem library design, and ligand selectivity/specificity classifications algorithms, as well as web-interfaced chemical databases and online data-mining tools (http://www.cbligand.org/CCGS/technology.php).
As a PI, Dr. Xie has four NIH funded projects with focus on GPCR chemical genomics, in-silico design/cheminformatics virtual screening method development, structure-diverse/target-focused library design, in vitro biovalidation and chemistry synthesis and recombinant GPCR membrane protein structural biology as well as small molecules for hematopoietic stem cell self-renewal. (www.CBLigand.org/xielab ) as below.
Project I. Structure and Function of CB2 Ligand and G-protein Recognition Pockets and GPCR Structure based CB2 Ligand Design (NIH R01DA025612, the PI, Xie. 04/10/10 - 03/31/15).
Project Team: Dr. Xiang-Qun (Sean) Xie (PI, Professor of Pharmaceutical Sciences), Dr. Stanley Opella (Professor at UCSD), Dr. Jurge Getsch (Professor at University of Bern).
This project is to characterize the cannabinoid receptor subtype 2 (CB2) binding residues and functional domains and then to elucidate 3D structures of the recognition pockets important to agonist/antagonist binding and G-protein coupling by combined biophysical and biochemical approaches.
Project II. Screen and Design p18INK4C Chemical Probes for Hematopoietic Stem Cell Self-Renewal (NIHR21HL109654, 07/01/2011-06/30/13, the PI, Xie)
Project Team: Dr. Xiang-Qun (Sean) Xie (PI, Professor of Pharmaceutical Sciences), Dr. Tao Cheng (Pittsburgh Cancer Institute, UPMC), and Dr. Lei Yang (Stem Cell Center, UPMC)
This project is to screen/design small drug molecules targeting CKI p18, and use them as chemical probes to explore the mechanisms of activating HSC self-renewal in increasing the quantity of functional stem cells. Ultimately, our work is to developing HSC drugs for therapeutic uses.
1) Xie, X.-Q.*; Chen, J.Z.; and Billings, E. “3D Structure Model of the G-Protein Coupled CB2 Cannabinoid Receptor” Proteins: Structure, Function, and Genetics, 53(2003), 307-319.
2) Xie, X-Q.*; Zheng, H.A. and Zhao, J. “Expression, purification, and isotope labeling of cannabinoid CB2 receptor fragment, CB2180-233” Protein Exp. & Purif. 38(2004), 61-68.(top 20 downloaded article in 2004).
3) X.-Q. Xie*, Chen, J.Z. “NMR Structural Comparison of the Cytoplasmic Juxtamembrane Domains of G-Protein Coupled CB1 and CB2 Receptors in Membrane-Mimetic DPC Micelles” Journal of Biol. Chem. 280(2005), 3605-3612
4) Xie, X-Q. Book Chapter 13, p.p 211-259, “Membrane Protein NMR” in “Structural Genomics on Membrane Proteins” (Editor, K. Lundstrom; (production editor, Joseph Stubenrauch) CRC Press (ISBC1-57444-526-X), Taylor & Francis Group, 2006
5) Zheng, H.A.; Zhao, J.; Sheng, W. Y. and Xie, X.-Q.* A transmembrane helix-bundle from G-protein coupled receptor CB2: biosynthesis, purification, and NMR characterization. Biopolymers (2006), 83(1), 46-61.
6) Zhang YX, Xie, ZJ, Wang, LR, Lazo, JS, Gertsch, J, Schribeit B, Xie X-Q*: Mutagenesis and computer modeling studies of a GPCR conserved residue W5.43(194) in ligand recognition and signal transduction for CB2 receptor. International Immunopharmacology 11(2011), 1303-10
Project III. NIH CMLD Center grant P50GM067082 (Wipf): New Concepts, Methodologies and Scaffolds for Diversity-Oriented Organic Synthesis (co-PI and Core Co-Director, Xie, 09/01/08-08/31/13)
Project Team: Peter Wipf (PI and Director), Kay Brummond, Dennis Curran, Paul Floreancig, Scott Nelson, Stephen Weber, Matt LaPorte and Xiang-Qun Xie (Pitt); David Beratan and Weitao Yang (Duke)
This project is to build a Pitt Center for Chemical Methodologies and Library Development (PCMLD). We will carry out the computational chemistry and cheminformatics projects defined in UP-CMLD by developing and applying our established computational chemical genomics approaches, including the following publications as examples.
Project IV. NIH/NCI/SAIC 29XS127 Task Order 6 (Huryn) Chemical Biology Consortium University of Pittsburgh Chemical Diversity Center (UPCDC) (Xie, co-PI and Director of Cheminformatics Core, 01/01/12-12/31/12)
The goal of this project is to identify and optimize inhibitors of STAT3 activation for use as potential drugs for the treatment of squamous cell carcinoma cancers of the head and neck. We have applied our developed computational chemical genomics approaches (www.CBLigand.org/CCGS) to interact with chemists and pharmacologists for design of structurally-diverse library or target-focused libraries, scaffold-hopping/R-group variation, high throughput docking and target/off-target prediction etc.
1) “GPU Accelerated Chemical Similarity Calculation for Compound Library Comparison”. Chao Ma, Lirong Wang, Xiang-Qun Xie. J. Chem. Inf. Model., 2011, 51 (7), pp 1521–1527
2) “Diverging DOS Strategy Using an Allene-Containing Tryptophan Scaffold and a Library Design that Maximizes Biologically Relevant Chemical Space While Minimizing the Number of Compounds.” Painter, Thomas O.; Wang, Lirong; Majumder, Supriyo; Xie, X.-Q.; Brummond, Kay M. ACS Combinatorial Science 13(2011), 166-174.
3) “Compound Acquisition and Prioritization (CAP) Algorithm for Constructing Structurally Diverse Chemical Libraries.” Ma, C, Xie, X-Q: J. Comb. Chem. 13(2011), 223-231.
4) “Residue Preference Mapping of Ligand Fragments in PDB” . Wang, L.R. Xie, ZJ, Wipf, Peter, and Xie*, X.-Q.* J. of Chem. Inf. and Modelings, 51(2011), 807-815.
5) “Construction of a Bicyclic beta -Benzyloxy and beta -Hydroxy Amide Library through a Multicomponent Cyclization Reaction.” Zhang L, Xiao Q, Ma C, Xie X-Q, Floreancig PE: J. Comb. Chem. 11 (2009), 640-644.
6) “A Diverging Rh(I)-Catalyzed Carbocylization Strategy to Prepare a Library of Unique Cyclic Ether.” Mao, S.L.; Probst, D.; Werner, S.; Chen, J.-Z.; Xie, X.-Q. and Brummond K. M. J. Combin. Chem., 10(2008), 235-246.
7) “UPCMLD-ChemBioData: Data-Mining Compound Bioactivity from PubChem”. Lirong Wang, Matt LaPorte, Peter Wipf, and Xiang-Qun (Sean) Xie. CMLD2011. 2011. Chicago.
8) “PAINS Remover- an online tool for Removal of Pan Assay Interference Compounds (PAINS)” ( http://cbligand.org/PAINS ). Lirong Wang, Peter Wipf, and Xiang-Qun Xie.
9) “Target Hunter –an online tool for target identification of small molecule” (http://cbligand.org/ TargetHunter). Lirong Wang, Peter Wipf, and Xiang-Qun (Sean) Xie.
10) “HTDocking-One Click for Drug Design”( http://cbligand.org/HTDocking ). Lirong Wang, Peter Wipf, and Xiang-Qun (Sean) Xie
1. Gertsch, J.; Leonti, M.; RadunerS.; RaczI.; Chen, J.-Z.; Xie, X.-Q.*; Altmann, K.; Zimmer, A.; Karsak, M. Beta-Caryophyllene is a Dietary Cannabinoid. PNAS 105(2008), 9099-9104.
2. Chen, J.; Wang, J.; and Xie, X.-Q.* “GPCR structure-based virtual screening approach for CB2 antagonist search.” J. Chemical Information and Modeling, 47(2007), 1626-1637.
3. Chen, JZ, Han, XW, Liu, Q, Makriyannis, A. Xie, X.-Q.* “3D QSAR Studies of Arylpyrazole Antagonists for CB1 and CB2 Cannabinoid Receptors. A Combined NMR and CoMFA Approach”, J. Med. Chem. 49(2006), 625-636.
4. Xie, X.-Q.*; Chen, J.Z.; and Billings, E. “3D Structure Model of the G-Protein Coupled CB2 Cannabinoid Receptor” Proteins: Structure, Function, and Genetics, 53(2003), 307-319.
5. Xie*, X.-Q.; Chen, J.Z. “Data-mining Small Molecule Drug Screening Representative Subset from NIH PubChem. J. of Chem. Inf. and Modelings, 48(2008), 465-475.
6. Mao, S.L.; Probst, D.; Werner, S.; Chen, J.-Z.; Xie, X.-Q.* and Brummond K. M. “A Diverging Rh(I)-Catalyzed Carbocylization Strategy to Prepare a Library of Unique Cyclic Ether.” J. Combin. Chem., 10(2008), 235-246.
7. Zhang, Y. and Xie, X.-Q.* “Biosynthesis, Purification and Characterization of a CB2 Protein Fragment (CB2271-326)” Protein Exp and Purif., 59(2008), 249-257.
8. Zheng, H.A.; Zhao, J.; Sheng, W. Y. and Xie, X.-Q.* A transmembrane helix-bundle from G-protein coupled receptor CB2: biosynthesis, purification, and NMR characterization. Biopolymers (2006), 83(1), 46-61.
9. Zhao, J. Zheng, H.A.; Jones, D.; Opella, S. and Xie, X.-Q.* "3D NMR characterization of cannabinoid receptor CB2 fragment CB2180-233" Protein and Peptide Letters 13(2006), 335-342.
10. X.-Q. Xie*, Chen, J.Z. “NMR Structural Comparison of the Cytoplasmic Juxtamembrane Domains of G-Protein Coupled CB1 CB2 Receptors in Membrane-Mimetic DPC Micelles” Journal of Biol. Chem. 280(2005), 3605-3612.