Cyclophilin A Inhibition: Targeting Transition-State-Bound Enzyme Conformations for Structure-Based Drug Design
Abstract
Human Cyclophilin A (CypA) catalyzes cis-trans isomerization of the prolyl peptide ω-bond in proteins and is involved in many subcellular processes. CypA has, therefore, been identified as a potential drug target in many diseases, and the development of potent inhibitors with high selectivity is a key objective. In computer-aided drug design, selectivity is improved by taking into account the inherent flexibility of the receptor. However, the relevant receptor conformations to focus on in order to develop highly selective inhibitors are not always obvious from available X-ray crystal structures or ensemble of conformations generated using molecular dynamics simulations. Here, we show that the conformation of the active site of CypA varies as the substrate configuration changes during catalytic turnover. We have analyzed the principal modes of the active site dynamics of CypA from molecular dynamics simulations to show that similar ensembles of enzyme conformations recognize diverse inhibitors and bind the different configurations of the peptide substrate. Small nonpeptidomimetic inhibitors with varying activity are recognized by enzyme ensembles that are similar to those that tightly bind the transition state and cis configurations of the substrate. Our results suggest that enzyme-substrate ensembles are more relevant in structure-based drug design for CypA than free enzyme. Of the vast conformational space of the free enzyme, the enzyme conformations of the tightly bound enzyme-substrate complexes are the most important for catalysis. Therefore, functionalizing lead compounds to optimize their interactions with the enzyme's conformational ensemble bound to the substrate in the cis or the transition state could lead to more potent inhibitors.
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A protein's biological function requires a conformational ensemble that is dictated by the energy landscape.
“more and more evidence indicates that the energy landscape dictates the conformational ensemble needed for the protein’s biological function.3”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [3]
Cites
Trott, O., & Olson, A. J. (2010) · Journal of Computational Chemistry · doi:10.1002/jcc.21334 · Cited by 38,412 · see citing works
Comparison of simple potential functions for simulating liquid water
Jorgensen, W. L., Chandrasekhar, J., Madura, J., Impey, R., & Klein, M. (1983) · The Journal of Chemical Physics · doi:10.1063/1.445869 · Cited by 38,335 · see citing works
Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems
Darden, T., York, D., & Pedersen, L. (1993) · The Journal of Chemical Physics · doi:10.1063/1.464397 · Cited by 29,588 · see citing works
Ryckaert, J., Ciccotti, G., & Berendsen, H. (1977) · Journal of Computational Physics · doi:10.1016/0021-9991(77)90098-5 · Cited by 19,525 · see citing works
A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules
Cornell, W. D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, K. M., Ferguson, D. M., Spellmeyer, D. C., Fox, T., Caldwell, J. W., & Kollman, P. A. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00124a002 · Cited by 13,111 · see citing works
Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030644s · Cited by 5,280 · see citing works
Kollman, P. A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Duan, Y., Wang, W., et al. (2000) · Accounts of Chemical Research · doi:10.1021/ar000033j · Cited by 4,978 · see citing works
Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A
Handschumacher, R. E., Harding, M. W., Rice, J. S., Drugge, R. J., & Speicher, D. W. (1984) · Science · doi:10.1126/science.6238408 · Cited by 1,675 · see citing works
The Many Roles of Computation in Drug Discovery
Jorgensen, W. L. (2004) · Science · doi:10.1126/science.1096361 · Cited by 1,560 · see citing works
Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins
Fischer, G., Wittmann‐Liebold, B., Lang, K., Kiefhaber, T., & Schmid, F. X. (1989) · Nature · doi:10.1038/337476a0 · Cited by 1,408 · see citing works
Molecular Dynamics: Survey of Methods for Simulating the Activity of Proteins
Adcock, S. A., & McCammon, J. A. (2006) · Chemical Reviews · doi:10.1021/cr040426m · Cited by 1,279 · see citing works
Cyclosporine induces cancer progression by a cell-autonomous mechanism
Hojo, M., Morimoto, T., Maluccio, M. A., Asano, T., Morimoto, K., Lagman, M., Shimbo, T., & Suthanthiran, M. (1999) · Nature · doi:10.1038/17401 · Cited by 1,148 · see citing works
Siekierka, J. J., Hung, S. H. Y., Poe, M., Lin, C. S., & SIGAL, N. H. (1989) · Nature · doi:10.1038/341755a0 · Cited by 1,007 · see citing works
Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease Inhibitors
Lam, P. Y. S., Jadhav, P. K., Eyermann, C. J., Hodge, C. N., Ru, Y., Bacheler, L. T., Meek, J. L., Otto, M. J., Rayner, M. M., Wong, Y. N., et al. (1994) · Science · doi:10.1126/science.8278812 · Cited by 835 · see citing works
Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B
Luban, J., Bossolt, K. L., Franke, E. K., Kalpana, G. V., & Goff, S. P. (1993) · Cell · doi:10.1016/0092-8674(93)90637-6 · Cited by 792 · see citing works
Crystal Structure of Human Cyclophilin A Bound to the Amino-Terminal Domain of HIV-1 Capsid
Gamble, T. R., Vajdos, F. F., Yoo, S., Worthylake, D. K., Houseweart, M., Sundquist, W. I., & Hill, C. P. (1996) · Cell · doi:10.1016/s0092-8674(00)81823-1 · Cited by 706 · see citing works
Prediction of Protein−Ligand Interactions. Docking and Scoring: Successes and Gaps
Leach, A. R., Shoichet, B. K., & Peishoff, C. E. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060999m · Cited by 648 · see citing works
A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance
Perola, E., Walters, W. P., & Charifson, P. S. (2004) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20088 · Cited by 446 · see citing works
TRANSITION STATE ANALOG INHIBITORS AND ENZYME CATALYSIS
Wolfenden, R. V. (1976) · Annual Review of Biophysics and Bioengineering · doi:10.1146/annurev.bb.05.060176.001415 · Cited by 416 · see citing works
Huang, S., & Zou, X. (2006) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21214 · Cited by 400 · see citing works
Computational Drug Design Accommodating Receptor Flexibility: The Relaxed Complex Scheme
Lin, J., Perryman, A. L., Schames, J. R., & McCammon, J. A. (2002) · Journal of the American Chemical Society · doi:10.1021/ja0260162 · Cited by 386 · see citing works
RAPAMYCIN FOR IMMUNOSUPPRESSION IN ORGAN ALLOGRAFTING
Calne, R. Y., Lim, S. M. L., Samaan, A., Collier, D. S., Pollard, S. G., White, D. J., & Thiru, S. (1989) · The Lancet · doi:10.1016/s0140-6736(89)90417-0 · Cited by 368 · see citing works
Peptidylprolyl Cis / Trans Isomerases (Immunophilins): Biological Diversity - Targets - Functions
Galat, A. (2003) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026033451862 · Cited by 360 · see citing works
Shen, J., Person, M. D., Zhu, J., Abbruzzese, J. L., & Li, D. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-3262 · Cited by 337 · see citing works
Representing Receptor Flexibility in Ligand Docking through Relevant Normal Modes
Cavasotto, C. N., Kovacs, J., & Abagyan, R. A. (2005) · Journal of the American Chemical Society · doi:10.1021/ja042260c · Cited by 279 · see citing works
McGovern, S. L., & Shoichet, B. K. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm0300330 · Cited by 276 · see citing works
Hamelberg, D., & McCammon, J. A. (2004) · Journal of the American Chemical Society · doi:10.1021/ja0377908 · Cited by 269 · see citing works
Self-citationEnzyme dynamics point to stepwise conformational selection in catalysis
Ma, B., & Nussinov, R. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.08.012 · Cited by 219 · see citing works
Water at biomolecular binding interfaces
Li, Z., & Lazaridis, T. (2006) · Physical Chemistry Chemical Physics · doi:10.1039/b612449f · Cited by 178 · see citing works
The Role of Water Molecules in Computational Drug Design
de Beer, S., Vermeulen, N., & Oostenbrink, C. (2010) · Current Topics in Medicinal Chemistry · doi:10.2174/156802610790232288 · Cited by 173 · see citing works
Lin, J., Perryman, A. L., Schames, J. R., & McCammon, J. A. (2002) · Biopolymers · doi:10.1002/bip.10218 · Cited by 169 · see citing works
Zhou, Z., Felts, A. K., Friesner, R. A., & Levy, R. M. (2007) · Journal of Chemical Information and Modeling · doi:10.1021/ci7000346 · Cited by 165 · see citing works
Craig, I. R., Essex, J. W., & Spiegel, K. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci900407c · Cited by 144 · see citing works
Dawson, T. M., Steiner, J. P., Lyons, W. E., Fotuhi, M., Blue, M. E., & Snyder, S. H. (1994) · Neuroscience · doi:10.1016/0306-4522(94)90389-1 · Cited by 137 · see citing works
Enthalpy of hydrogen bond formation in aprotein-ligand binding reaction.
Connelly, P. R., Aldape, R. A., Bruzzese, F. J., Chambers, S. P., Fitzgibbon, M. J., Fleming, M. A., Itoh, S., Livingston, D. J., Navia, M. A., & Thomson, J. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.5.1964 · Cited by 137 · see citing works
Chen, J., Xu, S. L., Wawrzak, Z., Basarab, G. S., & Jordan, D. B. (1998) · Biochemistry · doi:10.1021/bi981848r · Cited by 134 · see citing works
Sedrani, R. C., Kallen, J., Cabrejas, L. M. M., Papageorgiou, C. D., Senia, F., Rohrbach, S., Wagner, D., Thai, B., Jutzi-Eme, A.-M., France, J., et al. (2003) · Journal of the American Chemical Society · doi:10.1021/ja021327y · Cited by 117 · see citing works
Li, Z., Zhao, X., Bai, S., Wang, Z., Chen, L., Wei, Y., & Huang, C. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m700544-mcp200 · Cited by 114 · see citing works
Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A
Luo, C., Luo, H., Zheng, S., Gui, C., Yue, L., Yu, C., Sun, T., He, P., Chen, J., Shen, J., et al. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.07.003 · Cited by 109 · see citing works
Structures of Immunophilins and their Ligand Complexes
Dornan, J., Taylor, P., & Walkinshaw, M. D. (2003) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026033451899 · Cited by 106 · see citing works
Prolyl cis/trans isomerase signalling pathways in cancer
Theuerkorn, M., Fischer, G. S., & Schiene‐Fischer, C. (2011) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2011.03.007 · Cited by 104 · see citing works
Discovering Potent Small Molecule Inhibitors of Cyclophilin A Using de Novo Drug Design Approach
Ni, S., Yuan, Y., Huang, J. Y., Mao, X., Lv, M., Zhu, J., Shen, X., Pei, J., Lai, L., Jiang, H., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm9008295 · Cited by 96 · see citing works
Vajdos, F. F., Yoo, S., Houseweart, M. K., Sundquist, W. I., & Hill, C. P. (1997) · Protein Science · doi:10.1002/pro.5560061103 · Cited by 95 · see citing works
Predictive Power of Molecular Dynamics Receptor Structures in Virtual Screening
Nichols, S. E., Baron, R., Ivetac, A., & McCammon, J. A. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci200117n · Cited by 91 · see citing works
Doshi, U., & Hamelberg, D. (2009) · The Journal of Physical Chemistry B · doi:10.1021/jp907388m · Cited by 87 · see citing works
Self-citationBinding Free Energy Contributions of Interfacial Waters in HIV-1 Protease/Inhibitor Complexes
Lu, Y., Yang, C., & Wang, S. (2006) · Journal of the American Chemical Society · doi:10.1021/ja058042g · Cited by 84 · see citing works
Modeling correlated main‐chain motions in proteins for flexible molecular recognition
Zavodszky, M. I., Lei, M., Thorpe, M. F., Day, A., & Kuhn, L. A. (2004) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20179 · Cited by 79 · see citing works
Mikol, V., Papageorgiou, C., & Borer, X. (1995) · Journal of Medicinal Chemistry · doi:10.1021/jm00017a020 · Cited by 76 · see citing works
Resolving the complex role of enzyme conformational dynamics in catalytic function
Doshi, U., McGowan, L. C., Ladani, S. T., & Hamelberg, D. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117060109 · Cited by 75 · see citing works
Self-citationHOWARD, B. (2004) · Lung Cancer · doi:10.1016/j.lungcan.2004.05.013 · Cited by 71 · see citing works
Improving database enrichment through ensemble docking
Rao, S. N., Sanschagrin, P. C., Greenwood, J. R., Repasky, M. P., Sherman, W., & Farid, R. (2008) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-008-9182-y · Cited by 70 · see citing works
Isoform-Specific Inhibition of Cyclophilins
Daum, S., Schümann, M., Mathea, S., Aumüller, T., Balsley, M. A., Constant, S. L., de Lacroix, B. F., Kruska, F., Braun, M., & Schiene‐Fischer, C. (2009) · Biochemistry · doi:10.1021/bi9007287 · Cited by 69 · see citing works
Receptor Flexibility in de Novo Ligand Design and Docking
Alberts, I. L., Todorov, N. P., & Dean, P. M. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050196j · Cited by 64 · see citing works
Mechanistic Insight into the Role of Transition-State Stabilization in Cyclophilin A
Hamelberg, D., & McCammon, J. A. (2008) · Journal of the American Chemical Society · doi:10.1021/ja806146g · Cited by 62 · see citing works
Self-citationCyclophilin-A is involved in excitotoxin-induced caspase activation in rat neuronal B50 cells
Capano, M., Virji, S., & Crompton, M. (2002) · Biochemical Journal · doi:10.1042/bj3630029 · Cited by 46 · see citing works
Ensemble‐Docking Approach on BACE‐1: Pharmacophore Perception and Guidelines for Drug Design
Limongelli, V., Marinelli, L., Cosconati, S., Braun, H. A., Schmidt, B., & Novellino, E. (2007) · ChemMedChem · doi:10.1002/cmdc.200600314 · Cited by 42 · see citing works
García-Sosa, A. T., & Mancera, R. L. (2010) · Molecular Informatics · doi:10.1002/minf.201000007 · Cited by 39 · see citing works
Perryman, A. L., Lin, J., & McCammon, J. A. (2006) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2006.00382.x · Cited by 28 · see citing works
Synthesis and Biological Evaluation of Non-Peptidic Cyclophilin Ligands
Wu, Y., Belyakov, S. A., Choi, C., Limburg, D. C., Thomas, Vaal, M. J., Wei, L., Wilkinson, D. E., Holmes, A., Fuller, M., et al. (2003) · Journal of Medicinal Chemistry · doi:10.1021/jm020409u · Cited by 25 · see citing works
Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations
Acevedo, O., Ambrose, Z., Flaherty, P. T., Aamer, H., Jain, P., & Sambasivarao, S. V. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799436421 · Cited by 23 · see citing works
Computational Insight into Small Molecule Inhibition of Cyclophilins
Sambasivarao, S. V., & Acevedo, O. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci1004114 · Cited by 17 · see citing works
Goedken, E. R., & Marqusee, S. (1998) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19981001)33:1 · Cited by 11 · see citing works
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Wei, G., Xi, W., Nussinov, R., & Ma, B. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00562 · Cited by 436 · see citing works
Doshi, U., Holliday, M., Eisenmesser, E. Z., & Hamelberg, D. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523573113 · Cited by 167 · see citing works
Self-citationHonarparvar, B., Govender, T., Maguire, G. E. M., Soliman, M. E. S., & Kruger, H. G. (2013) · Chemical Reviews · doi:10.1021/cr300314q · Cited by 155 · see citing works
Simone, A. D., Georgiou, C., Ioannidis, H., Gupta, A. A., Juárez‐Jiménez, J., Doughty-Shenton, D., Blackburn, E. A., Wear, M. A., Richards, J. P., Barlow, P. N., et al. (2018) · Chemical Science · doi:10.1039/c8sc03831g · Cited by 33 · see citing works
Wapeesittipan, P., Mey, A. S. J. S., Walkinshaw, M. D., & Michel, J. (2019) · Communications Chemistry · doi:10.1038/s42004-019-0136-1 · Cited by 32 · see citing works
Magwenyane, A. M., Ugbaja, S. C., Amoako, D. G., Somboro, A. M., Khan, R. B., & Kumalo, H. M. (2022) · Computational and Mathematical Methods in Medicine · doi:10.1155/2022/2147763 · Cited by 30 · see citing works
Enhanced molecular dynamics sampling of drug target conformations
Rodriguez-Bussey, I., Doshi, U., & Hamelberg, D. (2015) · Biopolymers · doi:10.1002/bip.22740 · Cited by 27 · see citing works
Self-citationDetecting Functional Dynamics in Proteins with Comparative Perturbed-Ensembles Analysis
Yao, X., & Hamelberg, D. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00485 · Cited by 23 · see citing works
Self-citationRodriguez-Bussey, I., Yao, X., Shouaib, A., Lopez, J., & Hamelberg, D. (2018) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.8b03824 · Cited by 19 · see citing works
Self-citationLadani, S. T., Souffrant, M., Barman, A., & Hamelberg, D. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.12.023 · Cited by 18 · see citing works
Self-citationDrug resistance and tumor heterogeneity: cells and ensembles
Nussinov, R., Yavuz, B. R., & Jang, H. (2025) · Biophysical Reviews · doi:10.1007/s12551-025-01320-y · Cited by 17 · see citing works
Kumalo, H. M., Bhakat, S., & Soliman, M. E. S. (2015) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12582 · Cited by 15 · see citing works
Ladani, S. T., & Hamelberg, D. (2014) · Molecular Simulation · doi:10.1080/08927022.2014.919498 · Cited by 7 · see citing works
Self-citationWapeesittipan, P., Mey, A. S. J. S., Walkinshaw, M. D., & Michel, J. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/224329 · Cited by 3 · see citing works
Palaniappan, C., Rajendran, S., & Sekar, K. (2024) · Current Research in Structural Biology · doi:10.1016/j.crstbi.2024.100145 · Cited by 2 · see citing works
Tool and Techniques on Computer-Aided Drug Design for Targeted Cancer Therapy
Niveditha, V. G., Sindhu, V., Kizhakedathil, M. P. J., Sundari, I. S., & Balasubramaniyan, M. (2023) · Biological and medical physics, biomedical engineering · doi:10.1007/978-981-19-9786-0_23 · Cited by 1 · see citing works
Using Molecular Dynamics to Elucidate the Mechanism of Cyclophilin
McGowan, L. C. (2022) · Digital Archive @ GSU · doi:10.57709/5135066
Self-citationLadani, S. T. (2022) · Digital Archive @ GSU · doi:10.57709/6838121
- Authors
- Nagaraju, M., McGowan, L. C., & Hamelberg, D.
- Affiliations
- Georgia State University (US)
- Corresponding author
- Hamelberg, Donald
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-01-28
- Volume
- 53
- Issue
- 2
- Pages
- 403-410
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- OpenAlex
- W1978646878
- Cited by
- 18
- References
- 63
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 1
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Chemical Information and Modeling (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Georgia
- Georgia State University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- cyclophilin A, peptidyl-prolyl isomerase, active site dynamics, transition state binding, enzyme-substrate complex, substrate conformation, structure-based drug design, inhibitor selectivity, protein flexibility
- MeSH terms
- Enzyme Inhibitors, Humans, Protein Binding, Protein Conformation, Drug Design, Catalytic Domain, Cyclophilin A, Molecular Dynamics Simulation
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