6X3R
Human cyclophilin A bound to a series of acylcic and macrocyclic inhibitors
Summary for 6X3R
Entry DOI | 10.2210/pdb6x3r/pdb |
Descriptor | Peptidyl-prolyl cis-trans isomerase A, methyl (3~{S})-1-[(2~{S})-2-[[(2~{S})-2-acetamido-3-methyl-butanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]-1,2-diazinane-3-carboxylate (3 entities in total) |
Functional Keywords | cyclophilin a, sanglifehrin a, prolyl isomerase, macrocylcic inhibitor, peptidomimetic, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 1 |
Total formula weight | 18680.21 |
Authors | Appleby, T.C.,Paulsen, J.L.,Schmitz, U.,Shivakumar, D. (deposition date: 2020-05-21, release date: 2020-06-24, Last modification date: 2023-10-18) |
Primary citation | Paulsen, J.L.,Yu, H.S.,Sindhikara, D.,Wang, L.,Appleby, T.,Villasenor, A.G.,Schmitz, U.,Shivakumar, D. Evaluation of Free Energy Calculations for the Prioritization of Macrocycle Synthesis. J.Chem.Inf.Model., 60:3489-3498, 2020 Cited by PubMed Abstract: A tremendous research and development effort was exerted toward combating chronic hepatitis C, ultimately leading to curative oral treatments, all of which are targeting viral proteins. Despite the advantage of numerous targets allowing for broad hepatitis C virus (HCV) genotype coverage, the only host target inhibitors that advanced into clinical development were Cyclosporin A based cyclophilin inhibitors. While cyclosporin-based molecules typically require a fermentation process, Gilead successfully pursued a fully synthetic, oral program based on Sanglifehrin A. The drug discovery process, though greatly helped by facile crystallography, was still hampered by the limitations in the accuracy of predictive computational methods for prioritizing compound ideas. Recent advances in accuracy and speed of free energy perturbation (FEP) methods, however, are attractive for prioritizing and derisking synthetically challenging molecules and potentially could have had a significant impact on the speed of the development of this program. Here in our simulated prospective study, the binding free energies of 26 macrocyclic cyclophilin inhibitors were blindly predicted using FEP+ to test this hypothesis. The predictions had a low mean unsigned error (MUE) (1.1 kcal/mol) and accurately reproduced many design decisions from the program, suggesting that FEP+ has the potential to drive synthetic chemistry efforts by more accurately ranking compounds with nonintuitive structure-activity relationships (SARs). PubMed: 32539379DOI: 10.1021/acs.jcim.0c00132 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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