My current research efforts focus on applying computational and AI-based methods on drug design and on understanding biology. Upon designing a molecule or proposing a biological model, we work with collaborators to experimentally test it.
There are several research areas I'm interested in. First is to understand allosteric regulation of G-protein coupled receptors (GPCRs) and apply the knowledge to drug design targeting various GPCR members, in particular, those undruggable GPCR molecules. GPCRs represent the largest protein superfamily with more than 800 genes in human genome. GPCRs mediate cross membrane signaling and is the No. 1 drug target. GPCRs are naturally allosteric molecules. In recent years, developing allosteric drugs targeting the allosteric sites on GPCRs has attracted intensive interest. Current project includes designing small-molecule positive allosteric modulators of GLP-1R for treatment of type 2 diabetes and obesity.
The second research area is to use AI-based start-of-art protein design tools to design proteins or antibodies that bind to a protein of therapeutical interest such as T cell receptor.
The third research area is to utilize our expertise in computer-aided molecular design and bioinformatics to help researchers solve their biomedical problems.
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- BS (Tsinghua University)
- MS (Tsinghua University)
- PhD (Vanderbilt University)
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- Campbell J. A., Do P., Li Z., Malik F., Mead C., Miller N., Pisiechko C., Power K., and Li Z. Synthesis and biological studies of 2-aminothiophene derivatives as positive allosteric modulators of glucagon-like peptide 1 receptor. Bioorganic & Med. Chem. (2024) 111: 117864.
- Malik F. and Li Z. Is there a common allosteric binding site for G-protein coupled receptors? J. Computer-Aided Mol. Des. (2022) 36: 405-413.
- Redij T., McKee J.A., Do P., Campbell J. A., Ma J., Li Z., Miller N., Srikanlaya C., Zhang D., Hua X., Li Z. 2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor. Chem. Biology and Drug Design. (2022) 99(6): 857-867.
- Malik F. and Li Z. Non‐peptide agonists and positive allosteric modulators of glucagon‐like peptide‐1 receptor: alternative approaches for treatment of type 2 diabetes. British J. Pharmacology. (2022) 179(4): 511-525. (Invited Review).
- Regan K., Saghafi A., Li Z. Splice junction identification using long short-term memory neural networks. Current Genomics. (2021) 22(5): 384-390.
- Dang Z., Zhu L., Xie L., Lee K.-H., Malik F., Li Z., Huang L., Chen C-H. Design and synthesis of quinolizidine derivatives as influenza virus and HIV-1 Inhibitors. Current Med. Chem. (2021) 28(24): 4995-5003. PMID: 33372864.
- Redij T., Ma J., Li Z., Hua X., Li Z. Discovery of a potential positive allosteric modulator of glucagon-like peptide 1 receptor through virtual screening and experimental study. J. Computer-Aided Mol. Des. (2019) 33: 973-981.
- Gunderwala A., Nimbvikar A., Cope N., Li Z., Wang Z. Development of allosteric braf peptide inhibitors targeting the dimer interface of BRAF. ACS Chemical Biology (2019) 14: 1481-1489.
- Redij T., Chaudhari R., Li, Z., Hua X., Li Z. Structural Modeling and In SilicoScreening of Potential Small Molecule Allosteric Agonists of Glucagon-Like Peptide 1 Receptor. ACS Omega (2019) 4: 961-970.
- Mao B., Gao M., Chen C., Li Z., Zhang H.-Y., Zhang Q.. Design, synthesis and biological evaluation of novel N-nitrophenyl derivatives based on the structure of acetohydroxyacid synthase. Pesticide Biochemistry and Physiology. (2018) 145: 100-107.
- Dang Z., Xie H., Zhu L., Zhang Q., Li Z., Huang, L., Chen C.-H. Structure Optimization of Aloperine Derivatives as HIV-1 Entry Inhibitors. ACS Medicinal Chemistry Letters. (2017) 8: 1199-1203.
- Yuan X., Yang M., Chen X., Zhang X., Sukhadia S., Musolino N., Bao H., Chen T., Xu C., Wang Q., Santoro S., Ricklin D., Hu J., Lin R., Yang W., Li Z., Qin W., and Zhao A. Characterization of the first fully human anti-TEM1 scFv in models of solid tumor imaging and immunotoxin-based therapy. Cancer Immunol Immunother. (2017) 66(3): 367-378. Note: The figure from this publication showing the binding of scFv78 to human and murine TEM1, was featured on the cover of this issue of the Journal.
- Dong D., Xia G., Li Z., Li Z. Human serum albumin and her2-binding affibody fusion proteins for targeted delivery of fatty acid-modified molecules and therapy. Mol. Pharmacology (2016) 13(10): 3370-3380.
- Chaudhari R. and Li Z. PyMine: a PyMOL plugin to integrate and visualize data for drug discovery. BMC Research Notes (2015) 8: 517 DOI: 10.1186/s13104-015-1483-3.
- Chaudhari R., Heim A. J., and Li Z. Improving homology modeling of G-protein coupled receptors through multiple-template derived conserved inter-residue interactions. J. Computer-Aided Molecular Design (2015) 29: 413-420.
- Rogers B., Dong D., Li Z., and Li Z. Recombinant Human Serum Albumin Fusion Proteins and Novel Applications in Drug Delivery and Therapy. Curr Pharm Des. (2015) 21: 1899-1907.
- Menezes M.J., Guo Y., Zhang J., Riley L.G., Cooper S.T., Thorburn D.R., Li J., Dong D., Li Z., Glessner J., Davis R.L., Sue C.M., Alexander S.I., Arbuckle S., Kirwan P., Keating B.J., Xu X., Hakonarson H., Christodoulou J. Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure, and lactic acidemia. Hum. Mol. Genet. (2015) 24:2297-2307.
- I. Kufareva, V. Katritch, participants of GPCR Dock 2013 (Box 1), R. C. Stevens, and R. Abagyan, Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges. Structure (2014) 22: 1120-1139.
- S. Chaudhuri, S. Pratap, V. Paromov, Z. Li, and H. Xie. Identification of a diguanylate cyclase and its role in porphyromonas gingivalis virulence. Infection and Immunity (2014) 82(7): 2728-2735.
- A. J. Heim and Z. Li, Developing a high-quality scoring function for membrane protein structures based on specific inter-residue interactions. J. Computer-Aided Molecular Design (2012) 26: 301-309.
- J. Gao, Z. Li, T. Russelld, and Z. Li, Antibody affinity purification using metallic nickel particles. J. Chromatography B, (2012) 895–896: 89–93.
- V. Pabuwal and Z. Li, Comparison analysis of primary ligand binding sites in seven-helix membrane proteins. Biopolymers (2011) 95: 31-38.
- J. Gao and Z. Li, Uncover the conserved property underlying sequence-distant and structure-similar proteins. Biopolymers (2010) 93: 340-347.
- J. Gao and Z. Li, Conserved network properties of helical membrane protein structures and its implication for improving membrane protein homology modeling at the twilight zone. J. Computer-Aided Mol. Des. (2009) 23: 755-763.
- U. K. Muppirala, S. Desensi, T. P. Lybrand, G. L. Hazelbauer and Z. Li, Molecular modeling of flexible arm-mediated interactions between a bacterial chemoreceptor and its modification enzyme. Protein Sci. (2009) 18: 1702-1714.
- J. Gao and Z. Li, Comparing four different approaches for the determination of inter-residue interactions provides insight for the structure prediction of helical membrane proteins. Biopolymers (2009) 91: 547-556.
- V. Pabuwal and Z. Li, Comparative analysis of the packing topology of structurally important residues in helical membrane and soluble proteins. Protein Eng. Des. Sel. (2009) 22: 67-73.
- J. Gao and Z. Li, Inter-residue interactions in protein structures exhibit power-law behavior Biopolymers (2008) 89: 1174-1178.
- J. F. Galan, J. Gao, V. Pabuwal, P. J. Meek and Z. Li, Application of network theory in understanding and predicting protein structure and function. Current Proteomics (2008) 5(3): 181-190.
- W. Lai, L. Huang, P. Ho, Z. Li, D. Montefiori and C.-H. Chen, Small molecules target HIV-1 V3 loop with broad anti-HIV-1 entry activity. Antimicrob. Agents Chemother. (2008) 52: 128-136.
- V. Pabuwal and Z. Li, Network pattern of residue packing in helical membrane proteins and its application in membrane protein structure prediction. Protein Eng. Des. Sel. (2008) 21: 55-64.
- U. K. Muppirala and Z. Li, A simple approach for protein structure discrimination based on the network pattern of conserved hydrophobic residues. Protein Eng. Des. Sel. (2006) 19: 265-275.
- M. Dong, Z. Li, D. I. Pinon, T. P. Lybrand, and L. J. Miller, Spatial approximation between the amino terminus of a peptide agonist and the top of the sixth transmembrane segment of the secretin receptor. J. Bio. Chem. (2004) 279: 2894-2903.
- M. Dong*, Z. Li*, M. Zang, D. I. Pinon, T. P. Lybrand and L. J. Miller, Spatial approximation between two residues in the mid-region of secretin and the amino terminus of its receptor. Incorporation of seven sets of such constraints into a three-dimensional model of the agonist-bound secretin receptor. J. Bio. Chem. (2003) 278: 48300-48312. *Contributed equally
- M. Zang, M. Dong, D. I. Pinon, X.-Q. Ding, E. M. Hadac, Z. Li, T. P. Lybrand, and L. J. Miller, Spatial approximation between a photolabile residue in position 13 of secretin and the amino- terminus of the secretin receptor, Mol. Pharmacology (2003) 63: 993-1001.
- M. Dong, M. Zang, D. I. Pinon, Z. Li, T. P. Lybrand, and L. J. Miller, Interaction among four residues distributed through the secretin pharmacophore and a focused region of the secretin receptor amino terminus, Mol. Endocrinology (2002) 16: 2490-2501.
- Z. Li, L. Huang, P. Dande, B. Gold, and M. P. Stone, Structure of a tethered cationic 3-aminopropyl chain incorporated into an oligodeoxynucleotide: Evidence for 3 '-orientation in the major groove accompanied by DNA bending. J. Am. Chem. Soc. (2002) 124: 8553-8560.
- Z. Li, P. J. Tamura, A. S. Wilkinson, C. M. Harris, T. M. Harris, and M. P. Stone, Intercalation of the (1R,2S,3R,4S)-N-6-[1-(1,2,3,4-tetrahydro-2,3,4-trihydroxybenz[a]anthracenyl)]-2 '-deoxyadenosyl adduct in the N-ras codon 61 sequence: DNA sequence effects. Biochemistry (2001) 40: 6743-6755.
- Z. Li, H.-Y. Kim, P. J. Tamura, C. M. Harris, T. M. Harris, and M. P. Stone, Intercalation of the (1S,2R,3S,4R)-N-6[1-(1,2,3,4-tetrahydro-2,3,4-trihydroxybenz[alpha]anthracenyl)]-2 '-deoxyadenosyl adduct in an oligodeoxynucleotide containing the human N-ras codon 61 sequence. Biochemistry (1999) 38: 16045-16057.
- Z. Li, H.-Y. Kim, P. J. Tamura, C. M. Harris, T. M. Harris, and M. P. Stone, Role of a polycyclic aromatic hydrocarbon bay region ring in modulating DNA adduct structure: The non-bay region (8S,9R,10S,11R)-N-6-[11-(8,9,10,11-tetrahydro-8,9,10-trihydroxybenz[a] anthracenyl)]-2 '-deoxyadenosyl adduct in codon 61 of the human N-ras protooncogene. Biochemistry (1999) 38: 14820-14832.
- Z. Li, H. Mao, H.-Y. Kim, P. J. Tamura, C. M. Harris, T. M. Harris, and M. P. Stone, Intercalation of the (-)-(1R,2S,3R,4S)-N-6-[1-benz[a]anthracenyl]-2 '-deoxyadenosyl adduct in an oligodeoxynucleotide containing the human N-ras codon 61 sequence. Biochemistry (1999) 38: 2969-2981.
- S. Xu and Z. Li, Alignment mechanism of liquid crystal molecules on the fluorated polyimide surface. Tsinghua Science and Technology (1997) 2: 798-800.
- (Chinese) S. Xu and Z. Li, Study of alignment process technologies of liquid crystal molecules on surface of fluorated polyimide. Journal of Tsinghua University (Science and Technology) (1997) 37: 17-20.
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- W.W. Smith Charitable Trust (Role: PI) “Developing positive allosteric modulators of formyl peptide receptor 2 for the treatment of heart disease” $114,777, 01/01/2023-12/31/2023.
- NIH/NIAID – R01 (Role: Co-Investigator; PI: Dr. Chin-Ho Chen at Duke University) “New non-nucleoside reverse transcriptase inhibitors for drug resistant HIV strains” $1,555,006, Sub-award $299,192, 07/01/2021-06/30/2024.
- NIH/NIGMS – R15 and Supplement (Role: PI) “Is there a common allosteric binding site for all GPCRs?” $527,500, 09/15/2020-08/31/2023.
- NIH/NIAID – R01 (Role: Co-Investigator; PI: Dr. Chin-Ho Chen at Duke University) “Small molecule HIV-1 entry inhibitor with novel mechanisms of action” $1,276,953, Sub-award $113,000, 04/01/2018-03/31/2021.
- NIH/University of Pennsylvania – TAPITMAT (Role: Co-PI; PI: Dr. Xianxin Hua at University of Pennsylvania) “Developing small molecule allosteric agonists of glucagon-like peptide 1 receptor for diabetes therapy” $150,000, Sub-award $75,000, 02/01/2017-01/31/2020.
- NIH/NIAID – R56 (Role: Co-Investigator; PI: Dr. Chin-Ho Chen at Duke University) “Quinolizidines as novel HIV-1 entry inhibitors” $444,344, Sub-award $31,267, 08/17/2016-07/31/2017.
- NIH/University of Pennsylvania – TAPITMAT (Role: Co-PI; PI: Dr. Xiaolu Yang at University of Pennsylvania) “Targeting the p53-malic enzymes pathway for tumor therapy” $125,000, Sub-award $41,500, 02/01/2014-01/31/2016.
- NSF – MRI (Role: Co-PI; PI: Preston Moore) “Acquisition of a high performance CPU-GPU computer cluster for scientific computing at USciences”, $175,000, 09/01/2012-08/31/2015.
- Wistar-USciences CCBTM Pilot Project (Role: Co-PI; PI: Dr. Jose Conejo-Garcia at The Wistar Institute)“Development of non-immunosuppressive small molecule inhibitors of human PI3 kinases”, $50,000, Sub-award $25,000, 07/01/2012-06/30/2013.
- NIH/NIAID – R21 (Role: Co-Investigator; PI: Dr. Yuko Kimura at University of Pennsylvania) “Development of Small Molecule Inhibitors of Human Alternative Pathway” $251,512, Sub-award $73,387, 07/01/2010-06/30/2012.
- NIH/NIGMS – R15 (Role: PI) “Improve Homology Modeling for Membrane Proteins by Conserved Inter-residue Interactions” $231,630, 09/01/2009-08/31/2012.
- NIH/University of Pennsylvania – TAPITMAT (Role: Co-PI; Dr. Wenchao Song at University of Pennsylvania) “Development of Small Molecule Inhibitors of Human Complement Factor B” $150,000, Sub-award $75,000, 02/01/2009-01/31/2011
- NSF - Emerging Models and Technologies for Computation (Role: Co-PI; PI: Preston Moore) “Integration of Bioinformatics Modeling and Coarse Grain Dynamics: A New Computational Approach to Solve Complex Biological Problems” $275,000, 09/01/2006-08/31/2009.
- PhRMA Foundation (Role: PI) “Understanding Membrane Protein Packing through Network Analysis” $60,000, 01/2006–12/2007.