6X4P

Human cyclophilin A bound to a series of acylcic and macrocyclic inhibitors: (2R,5S,11S,14S,18E)-2,11,17,17-tetramethyl-14-(propan-2-yl)-15-oxa-3,9,12,26,29-pentaazatetracyclo[18.5.3.1~5,9~.0~23,27~]nonacosa-1(25),18,20(28),21,23,26-hexaene-4,10,13,16-tetrone (compound 28)

6X4P の概要

• エントリーDOI: 10.2210/pdb6x4p/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase A, (2R,5S,11S,14S,18E)-2,11,17,17-tetramethyl-14-(propan-2-yl)-15-oxa-3,9,12,26,29-pentaazatetracyclo[18.5.3.1~5,9~.0~23,27~]nonacosa-1(25),18,20(28),21,23,26-hexaene-4,10,13,16-tetrone (3 entities in total)
• 機能のキーワード: cyclophilin a, sanglifehrin a, prolyl isomerase, macrocylcic inhibitor, peptidomimetic, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18781.36

構造登録者

Appleby, T.C.,Paulsen, J.L.,Schmitz, U.,Shivakumar, D. (登録日: 2020-05-22, 公開日: 2020-06-24, 最終更新日: 2023-10-18)

主引用文献

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

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: 32539379
DOI: 10.1021/acs.jcim.0c00132

実験手法

X-RAY DIFFRACTION (1.5 Å)