个人简介

Ph.D. Molecular Biophysics, Oxford University, England, 1978 Molecular Genetics and Biochemistry Research Group Neurobiology and Behavior Research Group Molecular Genetics/Cell Physiology

研究领域

Structural Biology

The major research theme of my laboratory is to understand the molecular basis of disease and help to develop new treatment strategies. We study key regulatory proteins at the molecular level by applying the techniques of bioinformatics, biochemistry and crystallography to study the structure and function of protein-ligand complexes. Current research projects include: 1. Studies of drug resistance in HIV and comparative studies of other retroviruses. HIV and other retroviruses cause AIDS and cancer in humans and other animals. We are studying the crystal structures and enzymatic activities of drug resistant mutants of HIV proteases in order to understand the molecular basis for drug resistance. New protease inhibitors are studied as potential drug candidates to overcome resistance. Comparative studies on structure and substrate specificity are being performed on related proteases from Rous sarcoma virus and HTLV. 2. The Tcl1 family of proteins involved in chronic lymphocytic leukemias. We have determined the crystal structures of two members of the Tcl1 family of oncoproteins. These proteins fold into an eight-stranded beta barrel of unique topology. However, their role in lymphoid cell biology is not clear. 3. Bacterial carboxylesterases. We are studying the structures and activities of carboxylesterases from Geobacillus stearothermophilus . These enzymes are members of the serine hydrolase family and are related to physiologically important human enzymes. The crystal structure of Est30 showed a reaction intermediate and has provided insights into the reaction mechanism of this important family of enzymes. 4. Human glucokinase and mutations involved in type II diabetes. We have built models to understand how glucokinase binds to its two substrates, glucose and ATP. These glucokinase models have proved invaluable for understand the effects of glucokinase mutations involved in development of Mature Onset Diabetes of the Young.

近期论文

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Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. Ghosh AK, Brindisi M, Nyalapatla PR, Takayama J, Ella-Menye JR, Yashchuk S, Agniswamy J, Wang YF, Aoki M, Amano M, Weber IT, Mitsuya H. Bioorg Med Chem. 2017 Apr 9. pii: S0968-0896(17)30731-9. doi: 10.1016/j.bmc.2017.04.005. [Epub ahead of print] Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. Ghosh AK, Rao KV, Nyalapatla PR, Osswald HL, Martyr CD, Aoki M, Hayashi H, Agniswamy J, Wang YF, Bulut H, Das D, Weber IT, Mitsuya H. J Med Chem. 2017 May 25;60(10):4267-4278. doi: 10.1021/acs.jmedchem.7b00172. Epub 2017 Apr 18. Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation. Ghosh AK, Osswald HL, Glauninger K, Agniswamy J, Wang YF, Hayashi H, Aoki M, Weber IT, Mitsuya H. J Med Chem. 2016 Jul 28;59(14):6826-37. doi: 10.1021/acs.jmedchem.6b00639. Epub 2016 Jul 7. Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands. Ghosh AK, Martyr CD, Kassekert LA, Nyalapatla PR, Steffey M, Agniswamy J, Wang YF, Weber IT, Amano M, Mitsuya H. Org Biomol Chem. 2015 Dec 28;13(48):11607-21. doi: 10.1039/c5ob01930c. Epub 2015 Oct 14. Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies. Ghosh AK, Martyr CD, Osswald HL, Sheri VR, Kassekert LA, Chen S, Agniswamy J, Wang YF, Hayashi H, Aoki M, Weber IT, Mitsuya H. J Med Chem. 2015 Sep 10;58(17):6994-7006. doi: 10.1021/acs.jmedchem.5b00900. Epub 2015 Aug 25. Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies. Ghosh AK, Yu X, Osswald HL, Agniswamy J, Wang YF, Amano M, Weber IT, Mitsuya H. J Med Chem. 2015 Jul 9;58(13):5334-43. doi: 10.1021/acs.jmedchem.5b00676. Epub 2015 Jun 24. Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands. Ghosh AK, Takayama J, Kassekert LA, Ella-Menye JR, Yashchuk S, Agniswamy J, Wang YF, Aoki M, Amano M, Weber IT, Mitsuya H. Bioorg Med Chem Lett. 2015 Nov 1;25(21):4903-9. doi: 10.1016/j.bmcl.2015.05.052. Epub 2015 May 30. Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20. Agniswamy J, Louis JM, Shen CH, Yashchuk S, Ghosh AK, Weber IT. J Med Chem. 2015 Jun 25;58(12):5088-95. doi: 10.1021/acs.jmedchem.5b00474. Epub 2015 Jun 4.