As a School of Pharmacy faculty member, Dr. Sean Xie visionary leadership and innovation strategy has led to several research awards. Xie also served as a Charter Member of the Science Advisory Board to the US FDA. As Director/PI, Xie has led an NIH-funded Center of Excellence, a joint initiative between University of Pittsburgh and Carnegie Mellon University by creating fruitful collaborations that catalyze interdisciplinary research in the greater Pittsburgh area and beyond. As PI/Professor of an integrated MediChemBiology Lab, Xie also lead an AI computational drug design and discovery technology development team with over 190 publications in CELL, Nat. Comm, PNAS, JMC journals. He was co-PI/Core Director on three NIH center grants (P50 PCMLD, U54 PMLSC and NCI/SAIC). As Founder Director of Pharmacometrics Systems Pharmacology (PSP) program, Xie has developed a new education and research program for data science-driven PSP preclinical and clinical pharmacoanalytics. Overall, Xie has brought his expertise in machine-/deep-learning (ML/DL) chemogenomics systems pharmacology and medicinal chemistry drug design discovery into the cutting-edge translational R&D as well as clinical data mining and outcomes pharmacoanalytics as below.
As proof of our developed technologies above, Xie lab has published: i) 3D cryo-EM structure of cannabinoid receptor CB2/Gi signaling complex (Cell, 2020) and discovery of novel CB2 agonists, inverse agonists, neutral antagonists and allosteric modulators with therapeutic potential for cocaine-attenuation, kidney fibrosis and osteoporosis (5 patents, 3 JMC, 2 PNAS and Kidney Int.); ii) First-in-class p62-ZZ drug molecules (patents and Leukemia 2016, Nat Comm 2017, PNAS 2018); iii) First INK4C/p18-targeted drug (patent, 2015) for ex vivo expansion of murine and human hematopoietic stem cells (HSC) (Nat Comm 2015 and Sci Reports 2015). Xie received 2014 AAPS Award for Outstanding Research Achievements; and iv) the first on Nature Scientific Report about cardiovascular disease-specific chemogenomics knowledgebase-guided target identification and drug synergy mechanism study of a combination of herbal medications "Sini Decoction" (四逆汤). Xie received 2014 AAPS Award for Outstanding Research Achievements.
Xie has brought his expertise in AI machine-/deep-learning (ML/DL) chemogenomics systems pharmacology and medicinal chemistry drug design discovery into the cutting-edge translational R&D as well as clinical data mining and outcomes pharmacoanalytics. This includes GPU-accelerated chemogenomics-knowledgebased small molecule probe design and development for target-specific neurodisorders, multiple myeloma, osteoporosis and hematopoietic stem cell drug discovery by using integrated approaches of computational system pharmacology and virtual screening, structural biophysics, HTS bioassay validation and medicinal chemistry synthesis. His developed multidisciplinary research technology has led to his successful publication in 2020 CELL: 3D Cryo-EM Structure of Human Cannabinoid Receptor CB2-Gi Signaling Complex (PMID:32004460).
As proof of our developed technologies above, Xie lab has published: i) 3D cryo-EM structure of cannabinoid receptor CB2/Gi signaling complex (Cell, 2020) and discovery of novel CB2 agonists, inverse agonists, neutral antagonists and allosteric modulators with therapeutic potential for cocaine-attenuation, kidney fibrosis and osteoporosis (5 patents, 3 JMC, 2 PNAS and Kidney Int.); ii) First-in-class p62-ZZ drug molecules (patents and Leukemia 2016, Nat Comm 2017, PNAS 2018); iii) First INK4C/p18-targeted drug (patent, 2015) for ex vivo expansion of murine and human hematopoietic stem cells (HSC) (Nat Comm 2015 and Sci Reports 2015). Xie received 2014 AAPS Award for Outstanding Research Achievements
P30DA035778
Project Title: NIDA Center of Excellence OF Computational Drug Abuse Research (CDAR)
Funding Agency: National Institutes of Health (NIH, NIDA)
Investigator Relationship: P.I. and Center Director (X.-Q. Xie)
Dates of Funding 07/01/2014-06/31/2019
Annual Direct Costs and Overall Direct Costs: $1,126,949,000 and $5,960,391
Grant or Contract Research Grant
** To develop/integrate tools for DA-domain-specific chemical-to-protein-to-genomics mapping using cheminformatics, computational biology and computational genomics methods by centralizing computational chemical genomics (or chemogenomics) resources while also making them available on a cloud server. Overall, the Center will strive to achieve the long-term goal of translating advances in computational chemistry, biology and genomics toward the development of novel personalized DA therapeutics.
(Active)
R01DA025612 P.I.: X.-Q. Xie 4/1/2010-03/31/2016
Project Title: Structure/Function of the GPCR CB2 binding Pockets and G-protein Recognition Sites
Funding Agency: National Institutes of Health (NIDA)
Investigator Relationship: P.I. (X.-Q. Xie)
Dates of Funding 04/01/2010-03/31/2015 (active)
Annual Direct Costs and Overall Direct Costs: $250,000 and $1,250,000
Grant or Contract Research Grant
**The objective is to identify/characterize the key residues/functional domains and elucidate their 3D structures of recognition pockets important to agonist and antagonist binding as well as G-protein coupling recognitions in the CB2 receptor by the combined biophysical and biochemical approaches.
NIH R21 HL109654 P.I. X.-Q. Xie 7/1/2011-6/30/2014
Screen/Design the CKl p18 Inhibitors for Hematopoietic Stem Cell Self-Renewal
“This project is to screen/design small molecules targeting CKI p18, and use them as chemical probes for characterization of p18 protein binding and p18/CDK6 disruption, and further exploration of the mechanisms of activating HSC self-renewal in increasing the quantity of functional stem cells. Ultimately, our work will lead to developing HSC drugs for therapeutic uses.”
NIGMS P50 GM067082 (active) (Dr. Peter Wipf, Director)
Project Title: New Concepts, Methodologies and Scaffolds for Diversity-Oriented Organic Synthesis
Funding Agency: National Institutes of Health, NIGM
Investigator Relationship: Co-P.I./Core Co-Director (X.-Q. Xie)
Dates of Funding 10/01/08-09/30/14 (active)
Annual Direct Costs: $2,126,233, five years
Grant or Contract Research Grant
**The objective is to build a Pitt Center for Chemical Methodologies and Library Development (PCMLD) and design/develop diverse chemical library for NIH SML deposite.
NIH NCI/SAIC Contract No. 29XS127 (active) Co-PI X.-Q. Xie 9/1/2011-12/31/2013
University of Pittsburgh Chemical Diversity Center” (Donna M. Huryn, PI) (UP-CDC Project ID#1015)
The project is to conduct computational chemical genomics approach for STAT3 lead discovery and structurally-diverse library design."
1. GPU machine-/deep-learning (ML/DL) diseases-specific chemogenomics knowledgebases for systems pharmacology TargetHunter cannabinoid small-molecule drug discovery research.
1) Jing YK, Bian YM, Hu Zh, Xie X-Q. Deep Learning for Drug Design: An Artificial Intelligence Paradigm for Drug Discovery in the Big Data Era. AAPS J, 2018 20(3):58. PMID: 29603063
2) Bian Y, Wang J, Jun J Xie X.-Q.*, Deep convolutional generative adversarial network (dcGAN) models for screening and design of small molecules targeting cannabinoid receptors. Molecular pharmaceutics 2019, 16, 4451-4460. PMID: 31589460
3) Chen M, Jing Y, Feng Z*, and Xie X-Q*. DAKB-GPCRs: An Integrated Computational Platform for Drug Abuse Related GPCRs. J. Chem. Inf. Model. 2019, 59 (4):1283–1289. PMCID: PMC6758544
4) Bian Y, Jing Y, Ma S, Jun J, Xie, X.-Q.*. Prediction of orthosteric and allosteric regulations on cannabinoid receptors using supervised machine learning classifiers. Mol. pharm. 2019, 16, 2605-2615. PMID: 31013097
5) Wang L, Ma C, Wipf P, Liu H, Su W and Xie XQ*. “TargetHunter: An in-Silico Target Identification Tool for Predicting Therapeutic Potential of Small Organic Molecules Based on Chemogenomic Database”. AAPS J. 2013, 15, 395-406. PMID: 23292636 (AAPS Special theme issue)
6) Ma, C, Wang, LR, Xie, XQ*. i) “GPU Accelerated Chemical Similarity Calculation for Compound Library Comparison” J. Chem. Inf. Model., 51 (2011), 1521–1527. PMID: 21692447. ii) Ma C et al, “LiCABEDS II. Modeling of Ligand Selectivity for Cannabinoid Receptors”. JCIM, 2013, 53:11-26 PMID: 23278450
2. Computational Pharmacometrics System Pharmacology (PSP) investigation of clinical datamining pharmacoanalytics for substance abuse disorder (SUD) and neurological diseases (ND)
1) Jing Y, Hu Z, Fan P, Xue Y, Tarter RE, Kirisci L, Wang J, Vanyukov M, Ralph ET and Xie X-Q*. Analysis of Substance Use and Its Outcomes by Machine Learning I. Childhood Evaluation of Liability to Substance Use Disorder. Drug and Alcohol Dependence. 2020, 206: 107605; PMID: 31839402.
2) Hu Z, Jing Y, Xue Y, Fan P, Vanyukov M, Kirisci L, Wang J, Tarter RE and Xie X-Q*. Analysis of Substance Use and Its Outcomes by Machine Learning: II. Derivation and Prediction of the Trajectory of Substance Use Severity. Drug and Alcohol Dependence. 2020, 206:107604; PMID: 31615693.
3) Hu Z, Wang LR, Ma S, Kirisci L, Feng ZW, Xue Y, Klunk WE, Kamboh MI, Sweet RA, Becker J, Lv Q-z, Lopez OL*, and Xie X-Q*. Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease. Alzheimer's & Dementia: Trans Res & Clin Interv, 2018 4:542-555. PMID: 30386819.
4) Xue, Y.; Feng, ZW; Li, XY, Hu, ZH, Xu, Q, Wang, Z.; Cheng, JH, Xie, X.-Q.* and Lv, Q.-Z.*, “The efficacy and safety of cilostazol as an alternative to aspirin in Chinese patients with aspirin intolerance after coronary stent implantation: a combined clinical study and computational system pharmacology analysis.” Acta Pharmacologica Sinica (APS), 2018, 39: 205-212. PMID: 28933424
3. 3D CryoEM structure of cannabinoid receptor CB2 and structure-based drug design (CELL 2020)
1) Xing C, Zhuang Y, Xu T, Feng Z, Xu E, Zhang C and Xie XQ* Cryo-EM Structure of Human Cannabinoid Receptor CB2-Gi Signaling Complex. Cell, 2020,180(4):645-654, PMID:32004460.
2) Jordan CJ, Feng ZW, Galaj E, Bi GH, Xue Y, Liang Y, McGuire T, Xie XQ* and Xi ZX*. Xie2-64, a novel cannabinoid CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents. Neuropharmacology. 2020; 176: 108241. PMID: 32712273. (*Xie is co-correspondents).
3) Zhou L, Zhou S, Tian Y, Feng ZW, Xie X-Q*, Liu Y*. Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis. Kidney Int. 2018, 94(4):756-772. PMID: 30093080.
4) Bian Y, Jing Y, Ma S, Xie XQ*. Prediction of Orthosteric&Allosteric Regulations on Cannabinoid Receptors Using Supervised Machine Learning. Mol Pharm. 2019,16:2605-2615.PMID: 31013097.
5) Yang P, Wang L, Feng R, Almehizia AA, Myint KZ, Ouyang Q, Alqarni MH, Xie XQ*: “Novel triaryl sulfonamide derivatives as selective cannabinoid CB2 inverse agonists and osteoclast inhibitors: discovery, optimization, biological evaluation.” J Med Chem 2013, 56(5):2045-2058. PMID: 23406429
6) Feng RT, Tong Q, Xie Z, Wang L, Lentzsch S, Roodman GD, Xie XQ*: Targeting cannabinoid CB2 pathway by phenylacetylamide suppresses the proliferation of human myeloma cells through mitotic dysregulation and cytoskeleton disruption. Mol Carcinog 2015, 54:1796-806. PMID: 25640641.
4. First-in-class p62ZZ small-molecules with therapeutic potentials for neurodisorders and anti-tumors.
1) Cha-Molstad H, Yu Ji E, Kim Jung G, Hwang J, Ganipisetti S, Lee Kyung H, Kim Bo Y, Yu Ji E, Hong Jin T, Feng Z, Yang P, McGuire T, Wang N, Jang Jun M, Ciechanover A, Inhee MJ, Kwang PK, Xie X-Q*, Kwon YT*, & Kim, BY*. p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat Commun. 2017; 8:102. PMID: 28740232 (*Xie is a corresp.)
2) Teramachi J, Rebecca S, Anderson HL, Zhou D, Feng R, Myint KZ, Beumer JH, Eiseman, JL, Windle JL, Xie X-Q*, Roodman D*, Kurihara N*. “Blocking the ZZ Domain of Sequestosome1/p62 Suppresses Myeloma Cell Growth and Osteoclast Formation In Vitro and Induces Dramatic New Bone Formation in Myeloma-Bearing Bones In Vivo” Leukemia, 2016; 30:390-8. PMID: 26286116 (*Xie is a corresp.).
3) Yoo YD; Mun SR; Ji CH; Sung KW; Kang KY; Heo AJ; Lee SH; AN JK, HWANG J, Xie X-Q; Ciechanover A; Kim BY and Kwon YT. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. PNAS 2018; 115: E2716-E24. PMID: 2018:1229736.
4) Adamik J, Sun Q, Galson Deborah L, Silbermann R, Marino S, Anderson Judith L, Zhou D, Roodman GD, Silbermann R, Xie X-Q, Roodman GD. XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression. Frontiers in Endocrinology. 2018; 9:344. PMID: 30008697.
5. First INK4C/p18 chemical inhibitors for murine and human hematopoietic stem cell (HSC) expansion
1) Xie, XQ*, Yang P, Zhang Y, Zhang P, Wang L, Ding YH, Cheng HZ, McGuire T, Yuan WP, Cheng T and Gao YD. “Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion.” Scientific Reports (Nature), 2015, 5:18115.
2) Gao Y, Yang P, Shen HM, Yu H, Xie ZJ, Cheng T* and Xie XQ* “Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells”. Nature Communications, 2015, 6:6328. PMID: 25692908;
3) Zhang Y, Wang, LR, Feng ZW, Cheng T, Gao YD and Xie XQ* “StemCellCKB: An Integrated Stem Cell-Specific Chemogenomics Knowledge base for Target Identification and Systems-Pharmacology Research”, J Chem Inf Model. 2016, 56 (10), pp 1995–2004 DOI: 10.1021/acs.jcim.5b00748
4) Cheng T, Xie X, Gao Y (Patent) "p18 small molecule chemical inhibitor and human hematopoietic stem cell expansion ex vivo”. Patent No. 201510081641. 2015-06-12.
1) Xie, X-Q (Invited), “ID4Pharma LLC: Novel Target-specific Anti-Multiple Myeloma Drug Sequesta106®” in Venture Show Case Convention by joint initiative of NIH National Cancer Institute (NCI) Small Business Innovation Research (SBIR) center and Johnson & Johnson Innovation Center, Boston Innovation Center in Cambridge, MA. June 19-20, 2019, Boston Cambridge, MA.
2) Xie, X-Q (invited). “Chemogenomics Systems Pharmacology Approach for TBI and AD Research”. FY19 PRARP in Progress Review Annual Meeting, DOD grant Contract #: W81XWH-16-1-0490. Sept 29, 2019. 1076 Patchel Street, Fort Detrick, MD 21702.
3) Xie, X-Q (invited), Charter Member of the FDA Science Advisory Board meeting. FDA White Oak Campus, Building 31, The Great Room (Rm. 1503). 10903 New Hampshire Ave, Silver Spring, Maryland 20993. October 7, 2019.
4) Xie X-Q (Invited). “Pharmacometrics & System Pharmacology(PSP) -- An Integrated PSP Platform of GPU Computational Chemogenomics Knowledgebased Drug Discovery. ” The 6th Clarivate China Pharmaceutical Industry Conference 29-30 August 2019, in Beijing, China.
5) (Invited speaker) Xie, XQ, 2017 Feb 2nd, “An Integrated Platform of “big data to knowledge” Diseases-Specific Chemogenomics Knowledgebases and TargetHunter©” Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033
6) (Invited speaker) Xie, XQ, 2016, Oct 24, “Precision Medicine via Chemogenomics Knowledgebase TargetHunter© --- Alzheimer’s disease drug research from bench top to beside”, Biogen Inc. Building 6 (115 Broadway, Cambridge MA 02142
7) (Invited speaker) Xie, XQ, 2016 Feb 2, “Precision Pharmacology Benchtop to Bedside: Thinking inside Precision Medicine via Diseases-Specific Chemogenomics Knowledgebases and TargetHunter©” College of Pharmacy, University of Georgia, Atlanta, Georgia
8) (Invited speaker) Xie, XQ, 2016 May 27, “Clinical System Pharmacology by Chemogenomics Knowledgebase”, 2016 Sino-America Forum of Clinical Pharmacy at Fudan University, China
2) (Invited speaker) Xie, XQ, 2016 June 4 “Benchtop to Bedside” Precision System Pharmacology by Chemogenomics Knowledgebases and TargetHunter©” Tasly R&D Institute, China
3) (Invited speaker) Xie, XQ, 2016 June 3, “Precision System Pharmacology. A Case Study “Benchtop to Bedside” of Alzheimer’s Disease (AD) via Chemogenomics Knowledgebases and TargetHunter©”, Medicinal Chemistry Biology Key Laboratory, Nankai University, China
4) (Invited speaker) Xie, XQ, 2016 June 13, “Stem Cells-specific Chemogenomics Knowledgebase and Discovery of First INK4C Chemical Modulator for Hematopoietic Stem Cell Expansion”, Seoul National University, South Korea.
5) (Invited speaker) Xie, XQ, 2016 June 16, “Precision Pharmacology. Thinking inside Precision Medicine via Diseases-Specific Chemogenomics Knowledgebases and TargetHunter©”. 2016 Bit’s 14th Annual Congress of International Drug Discovery Science and Technology, June 16-18, Gyeonggi, South Korea.
6) (Invited speaker) Xie, XQ, 2016 June 20, “GPU-accelerated Cloud Computing Chemogenomics Knowledgebases and TargetHunter© for Precision System Pharmacology and Drug Discovery” Guangzhou Branch of Chinese Academy of Sciences, Guangdong, China
7) Invited Speaker, 2016 Jan 20 “Short-Term and Long-Term Strategic Plans and Execution”, College of Pharmacy, University of Hawaii, Hilo, Hawaii.
8) Invited speaker, 2016, January 27, “Precision System Pharmacology for Multiple Myeloma and Osteoporosis: Thinking Inside Precision Medicine via Diseases-Specific Chemogenomics Knowledgebases and TargetHunter©”, Pittsburgh Center for Bone & Mineral Research Seminar Series, University of Pittsburgh.
9) Speaker and organizing committee chair, symposium “Pharmaceutical Sciences in the Era of Big Data” 2015 AAPS Annual meeting, Orlando, Florida, USA. October 21-26, 2015
10) Speaker/Chair, “Computational Chemogenomics Knowledgebase for Drug Abuse Research”, National Center for Computational Drug Abuse Research (CDAR), May 14, 2015
11) Invited Speaker 2015 April 10, “Diseases-Specific Chemogenomics Knowledgebases and TargetHunter© for System Pharmacology and Alzheimer’s Disease Drug Discovery Research”, FDA - Center for Devices and Radiological Health, Office of Science and Engineering Laboratories , Division of Biology, Chemistry, and Materials Science, Silver Spring, MD, USA
12) Invited Speaker 2015 March 12, “Diseases-Specific Chemogenomics Knowledgebases and TargetHunter© for System Pharmacology and Alzheimer’s Disease Drug Discovery Research” Alzheimer’s Disease Clinical Research Center, School of Medicine, University of Pittsburgh, PA
13) Invited Speaker 2015 Feb “Diseases-Specific Chemogenomics Knowledgebases and Drug TargetHunter© Center for Drug Discovery (CDD), School of Pharmacy, Northeastern University, Boston, MA USA
14) Invited Speaker 2015 Jan 30, “Diseases-Specific Chemogenomics Knowledgebases and TargetHunter© for Quantitative System Pharmacology” Department of Informatics, University of Pittsburgh, PA
15) Invited Speaker 2014 “Cloud Computing and Diseases-Specific Chemogenomics Knowledgebase for System Pharmacology Drug Discovery and Personalized Medicine” at New Frontiers in Therapeutic Agents – Successes in Drugging the Undruggable Conference, jointly sponsored by the John S. Dunn Gulf Coast Consortium for Chemical Genomics (GCCCG) and the Texas Screening Alliance for Cancer Therapeutics (TxSACT). April 16-17, 2014, The University of Texas MD Anderson Cancer Center, Houston, Texas. USA.
16) Invigted Speaker 2014 ”Manipulation of Hematopoietic Stem Cell Expansion by INK4C Chemical Inhibitors” December 18, 2014, Stem Cell Research Center, University of Pittsburgh, Pittsburgh USA
17) In vited Speaker 2014 ”Cloud Computing Target Hunter and Disease-Specific Chemogenomics Knowledgebase for System Pharmacology Drug Discovery and Personalized Medicine”. June 23, 2014 University of Florida, Gainseville, Florida, USA
18) Invited 2013 ”Cloud Computing and Diseases Domain-Specific Chemogenomics Knowledgebases for Systems Pharmacotherapy and Personalized Medicine.” Workshop on Quantitative Systems Pharmacology in Personalized Medicine. Nov. 2013, Pittsburgh, USA.
19) Invited seminar speaker, April 24, 2012, “Computational Chemical Genomics Screening Center” Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
20) Invited speaker, March, 28, 2012, “Computational Chemical Genomics Screening Center”, Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
21) Invited speaker, December 19, 2011 “GPCR Chemical Genomics for Drug Discovery”, Shanghai JiaoTong University, College of Pharmacy, Shanghai, China
22) Invited speaker, December 28, 2011 “Computational GPCR Chemical Genomics for Drug Discovery”, Sun-Yat Sen University, College of Life Sciences, Guangzhou, China
23) Invited speaker, July 28, 2011 “GPCR Chemical Genomics for Drug Discovery”, Shanghai NanKai University, College of Pharmacy, Tianjin, China
24) Invited speaker, June, 10, 2012, “Cloud computing and High Throughput Experimental Chemical Genomics Screening Approaches for Lead Discovery”, Jinan University, GuangZhou, China
25) Invited speaker, June, 20, 2012, “Cloud computing and High Throughput Experimental Chemical Genomics Screening Approaches for Natural Product Target Identification and Lead Discovery”, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
26) Invited speaker, June, 23, 2012, “Computational Chemical Genomics Screening Approaches for Natural Product Target Identification and Lead Discovery”, XiShuanBanNan Tropical Botanic Garden, Chinese Academy of Sciences, XiShuanBanNan, China"
(Active)
NIH NIDA P30 DA035778-01A1 (Xie and PI/Center Director)
7/1/2014 - 6/30/2019 $5,960,391
NIDA Center of Excellence for Computational Drug Abuse Research (CDAR)
New awarded DOD grant AZ150100 (PI Dr. Xiang-Qun Xie) letter of award received.
9/1/2016-8/31/2019
Chemogenomics Systems Pharmacology Approach for TBI and AD Research
