Dr. Craft's work incorporates molecular modeling, simulation, quantum mechanics, and computational biophysics to develop and refine drug development processes, with regular forays into materials science and polymer chemistry. He has deployed his computational expertise in a broad range of drug discovery efforts, from anti-inflammatory compounds, to anti-virals, to modulators of integrin activity. His research activities contribute to the development of therapeutics for infectious diseases, cardiovascular disease, and some types of cancer. Dr. Craft's research program thus contributes to advances in drug discovery, one of the major research priorities at the University of Houston.
Figure 1: Our work flow takes drug design from cradle to phase A and possible commercialization. We iterate over millions of compounds in silico to generate hundreds of leads that are selected by our collaborators at the Texas Heart Institute for synthesis and testing in human cells, pathway specific assays, and binding analysis. Our current project has synthesized and test 205 unique compounds. over 12 have confirmed efficacy and are undergoing further refinement.
::Spleen Tyrosine Kinase (SYK)
Atherosclerotic Cardiovascular Disease is characterized by plaque buildup in arteries. IL-1β is an inflammatory cytokine and is a clinically validated target molecule in this pathway. Three seminal studies, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LODOCO2), and the Colchicine Cardiovascular Outcomes Trial (COLCOT), have proven the hypothesis that atherosclerosis is an inflammatory disease, and that targeting mechanisms of inflammation can reduce major adverse cardiac events independent of lipid lowering. Integrin signaling through the Spleen Tyrosine Kinase (SYK) is essential for IL-1β production and motivation our Drug Discovery program. A structure based computational screen of 15+ million compounds identified 1037 compounds clustered into five families based on their energy scores, functional groups and Tanimoto scores. Datamining this information using GAUSSIAN, AUTODOCK, GROMACS, and PYTHON tools through the University of Houston computing clusters and on AZURE cloud and streamlined scripts built in CHAT-GPT and GROK3 with follow on analysis of the compounds visually in pyMOL have lead to continue refinement of our hypothesis. A prevalent number of compounds interact with GLU242 and ARG45 along the proposed locus of interface residues. 205 compounds have been synthesized and submitted for integrin signaling assay, integrin/SYK elisa, and FcγRI signaling controls. Three classes of compounds have met the potency metric for identifying hits (10 uM in the integrin signaling assay). Analogs of these classes have been designed and synthesized to develop structure activity relationships (SAR). Docked structures and molecular dynamics simulations will be evaluated in-depth to rationally design compounds that have more favorable protein-small molecule interactions.
Figure 2: We are developing lead compound that bind to SYK.
Bakthavatsalam D, Craft JW Jr, Kazansky A, Nguyen N, Bae G, Caivano AR, Gundlach CW 4th, Aslam A, Ali S, Gupta S, Lin SY, Parthiban HD, Vanderslice P, Stephan CC, Woodside DG.
Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.
Front Immunol.
2020;132(13).
doi: 10.3389/fimmu.2020.575085. PubMed PMID:
33488575 ; PubMed Central PMCID:
PMC7819857 .
::Integrins
The inability of CD8+ T effectors (Teff) to reach tumor cells is an important mechanism of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that is expressed on T cells. Here we show that 7HP349, a small molecule activator of Lymphocyte function–associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin-cell- adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improve antitumor response. 7HP349 monotherapy had modest effects on anti programmed death (PD-1) resistant tumors, whereas combinatorial treatment with anti T-lymphocyte- associated protein 4 (CTLA-4) therapy increased CD8+ Teff intratumoral sequestration and synergized in inducing cancer regression, in cooperation with neutrophils. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression may improve response likelihood to anti-CTLA-4 therapies. Our results provided a proof-of-principle demonstration that LFA-1 activation could convert a T cell-exclusionary TME to a T-cell enriched TME through mechanisms involving cooperation with innate immune cells.
Hickman A, Koetsier J, Kurtanich T, Nielsen MC, Winn G, Wang Y, Bentebibel SE, Shi L, Punt S, Williams L, Haymaker C, Chesson CB, Fa'ak F, Dominguez AL, Jones R, Kuiatse I, Caivano AR, Khounlo S, Warier ND, Marathi U, Market RV, Biediger RJ, Craft JW Jr, Hwu P, Davies MA, Woodside DG, Vanderslice P, Diab A, Overwijk WW, Hailemichael Y.
LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade.
J Clin Invest.
2022 Jul 1;132(13).
doi: 10.1172/JCI154152. PubMed PMID:
35552271; PubMed Central PMCID:
PMC9246385.
