Cyclophilin D (CypD) is a key regulator of mitochondrial permeability transition pore (mPTP) opening. This pathophysiological phenomenon is associated with the development of several human diseases, including ischemia-reperfusion injury and neurodegeneration. Blocking mPTP opening through CypD inhibition could be a novel and promising therapeutic approach for these conditions. While numerous CypD inhibitors have been discovered to date, none have been introduced into clinical practice, mostly owing to their high toxicity, unfavorable pharmacokinetics, and low selectivity for CypD over other cyclophilins. This review summarizes current knowledge of CypD inhibitors, with a particular focus on small-molecule compounds with regard to their in vitro activity, their selectivity for CypD, and their binding mode within the enzyme's active site. Finally, approaches for improving the molecular design of CypD inhibitors are discussed.

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

University Hospital Hradec Kralove Biomedical Research Centre Hradec Kralove Czech Republic

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Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005;434:652-658. doi:10.1038/nature03317

Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005;434:658-662. doi:10.1038/nature03434

Elrod JW, Molkentin JD. Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore. Circ J Off J Jpn Circ Soc. 2013;77:1111-1122.

Bernardi P, Rasola A, Forte M, Lippe G. The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol Rev. 2015;95:1111-1155. doi:10.1152/physrev.00001.2015

Šileikytė J, Forte M. The mitochondrial permeability transition in mitochondrial disorders. Oxid Med Cell Longev. 2019;2019:3403075. doi:10.1155/2019/3403075

Alam MR, Baetz D, Ovize M. Cyclophilin D and myocardial ischemia-reperfusion injury: a fresh perspective. J Mol Cell Cardiol. 2015;78:80-89. doi:10.1016/j.yjmcc.2014.09.026

Bonora M, Patergnani S, Ramaccini D, et al. Physiopathology of the permeability transition pore: molecular mechanisms in human pathology. Biomolecules. 2020;10:998. doi:10.3390/biom10070998

Halestrap AP, Richardson AP. The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol. 2015;78:129-141. doi:10.1016/j.yjmcc.2014.08.018

Sun J, Ren DD, Wan JY, et al. Desensitizing mitochondrial permeability transition by ERK-cyclophilin D axis contributes to the neuroprotective effect of gallic acid against cerebral ischemia/reperfusion injury. Front Pharmacol. 2017;8:184. doi:10.3389/fphar.2017.00184

Chouchani ET, Pell VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431-435. doi:10.1038/nature13909

Bibli SI, Papapetropoulos A, Iliodromitis EK, et al. Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug. Cardiovasc Res. 2019;115:625-636. doi:10.1093/cvr/cvy222

Benek O, Aitken L, Hroch L, Kuca K, Gunn-Moore F, Musilek K. A direct interaction between mitochondrial proteins and amyloid-β peptide and its significance for the progression and treatment of Alzheimer's disease. Curr Med Chem. 2015;22:1056-1085. doi:10.2174/0929867322666150114163051

Valasani KR, Sun Q, Fang D, et al. Identification of a small molecule cyclophilin D inhibitor for rescuing Aβ-mediated mitochondrial dysfunction. ACS Med Chem Lett. 2016;7:294-299. doi:10.1021/acsmedchemlett.5b00451

Rao VK, Carlson EA, Yan SS. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta. 2014;1842:1267-1272. doi:10.1016/j.bbadis.2013.09.003

Warne J, Pryce G, Hill JM, et al. Selective inhibition of the mitochondrial permeability transition pore protects against neurodegeneration in experimental multiple sclerosis. J Biol Chem. 2016;291:4356-4373. doi:10.1074/jbc.M115.700385

Shore ER, Awais M, Kershaw NM, et al. Small molecule inhibitors of cyclophilin D to protect mitochondrial function as a potential treatment for acute pancreatitis. J Med Chem. 2016;59:2596-2611. doi:10.1021/acs.jmedchem.5b01801

Mukherjee R, Mareninova OA, Odinokova IV, et al. Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut. 2016;65:1333-1346. doi:10.1136/gutjnl-2014-308553

Bonora M, Pinton P. The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Front Oncol. 2014;4:302. doi:10.3389/fonc.2014.00302

Milduberger N, Bustos PL, González C, Perrone AE, Postan M, Bua J. Trypanosoma cruzi infection in cyclophilin D deficient mice. Exp Parasitol. 2021;220:108044. doi:10.1016/j.exppara.2020.108044

Wang X, Du H, Shao S, et al. Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis. Hepatology. 2018;68:62-77. doi:10.1002/hep.29788

Ure DR, Trepanier DJ, Mayo PR, Foster RT. Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29:163-178. doi:10.1080/13543784.2020.1703948

Sileikyte J, Roy S, Porubsky P, et al. Small molecules targeting the mitochondrial permeability transition. In: Probe Reports from the NIH Molecular Libraries Program. National Center for Biotechnology Information (US); 2010. Accessed October 26, 2020. http://www.ncbi.nlm.nih.gov/books/NBK280049/

Panel M, Ruiz I, Brillet R, et al. Small-molecule inhibitors of cyclophilins block opening of the mitochondrial permeability transition pore and protect mice from hepatic ischemia/reperfusion injury. Gastroenterology. 2019;157:1368-1382. doi:10.1053/j.gastro.2019.07.026

Nesci S. The mitochondrial permeability transition pore in cell death: a promising drug binding bioarchitecture. Med Res Rev. 2020;40:811-817. doi:10.1002/med.21635

Shevtsova EF, Maltsev AV, Vinogradova DV, Shevtsov PN, Bachurin SO. Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease. Med Res Rev. 2021;41:803-827. doi:10.1002/med.21715

Bauer TM, Murphy E. Role of mitochondrial calcium and the permeability transition pore in regulating cell death. Circ Res. 2020;126:280-293. doi:10.1161/CIRCRESAHA.119.316306

Amanakis G, Murphy E. Cyclophilin D: an integrator of mitochondrial function. Front Physiol. 2020;11:595. doi:10.3389/fphys.2020.00595

Porter GA, Beutner G. Cyclophilin D, somehow a master regulator of mitochondrial function. Biomolecules. 2018;8:176. doi:10.3390/biom8040176

Amodeo GF, Pavlov EV. Amyloid β, α-synuclein and the c subunit of the ATP synthase: can these peptides reveal an amyloidogenic pathway of the permeability transition pore? Biochim Biophys Acta BBA-Biomembr. 2021;1863:183531. doi:10.1016/j.bbamem.2020.183531

Briston T, Selwood DL, Szabadkai G, Duchen MR. Mitochondrial permeability transition: a molecular lesion with multiple drug targets. Trends Pharmacol Sci. 2019;40:50-70. doi:10.1016/j.tips.2018.11.004

Halestrap AP, Davidson AM. Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J. 1990;268:153-160. doi:10.1042/bj2680153

Connern CP, Halestrap AP. Purification and N-terminal sequencing of peptidyl-prolyl cis-trans-isomerase from rat liver mitochondrial matrix reveals the existence of a distinct mitochondrial cyclophilin. Biochem J. 1992;284(Pt 2):381-385. doi:10.1042/bj2840381

Davis TL, Walker JR, Campagna-Slater V, et al. Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. PLoS Biol. 2010;8:e1000439. doi:10.1371/journal.pbio.1000439

Hopkins S, Gallay P. Cyclophilin inhibitors: an emerging class of therapeutics for the treatment of chronic hepatitis C infection. Viruses. 2012;4:2558-2577. doi:10.3390/v4112558

Rycyzyn MA, Reilly SC, O'Malley K, Clevenger CV. Role of cyclophilin B in prolactin signal transduction and nuclear retrotranslocation. Mol Endocrinol. 2000;14:1175-1186. doi:10.1210/mend.14.8.0508

Ahmed-Belkacem A, Colliandre L, Ahnou N, et al. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities. Nat Commun. 2016;7:12777. doi:10.1038/ncomms12777

DeLano WL.The PyMOL Molecular Graphics System, Version 1.2r3pre. Schrödinger, LLC; n.d.

Lebedev I, Nemajerova A, Foda ZH, et al. A novel in vitro CypD-mediated p53 aggregation assay suggests a model for mitochondrial permeability transition by chaperone systems. J Mol Biol. 2016;428:4154-4167. doi:10.1016/j.jmb.2016.08.001

Pestana CR, Silva CHTP, Uyemura SA, Santos AC, Curti C. Impact of adenosine nucleotide translocase (ANT) proline isomerization on Ca2+-induced cysteine relative mobility/mitochondrial permeability transition pore. J Bioenerg Biomembr. 2010;42:329-335. doi:10.1007/s10863-010-9297-4

Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999;341(Pt 2):233-249.

Leung AWC, Varanyuwatana P, Halestrap AP. The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem. 2008;283:26312-26323. doi:10.1074/jbc.M805235200

He L, Lemasters JJ. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett. 2002;512:1-7. doi:10.1016/S0014-5793(01)03314-2

Giorgio V, von Stockum S, Antoniel M, et al. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA. 2013;110:5887-5892. doi:10.1073/pnas.1217823110

Alavian KN, Beutner G, Lazrove E, et al. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci USA. 2014;111:10580-10585. doi:10.1073/pnas.1401591111

Fayaz SM, Raj YV, Krishnamurthy RG. CypD: the key to the death door. CNS Neurol Disord Drug Targets. 2015;14:654-663. doi:10.2174/1871527314666150429113239

Brustovetsky N. The role of adenine nucleotide translocase in the mitochondrial permeability transition. Cells. 2020;9:2686. doi:10.3390/cells9122686

Menazza S, Wong R, Nguyen T, Wang G, Gucek M, Murphy E. CypD−/− hearts have altered levels of proteins involved in Krebs cycle, branch chain amino acid degradation and pyruvate metabolism. J Mol Cell Cardiol. 2013;56:81-90. doi:10.1016/j.yjmcc.2012.12.004

Shang W, Gao H, Lu F, et al. Cyclophilin D regulates mitochondrial flashes and metabolism in cardiac myocytes. J Mol Cell Cardiol. 2016;91:63-71. doi:10.1016/j.yjmcc.2015.10.036

Laker RC, Taddeo EP, Akhtar YN, Zhang M, Hoehn KL, Yan Z. The mitochondrial permeability transition pore regulator cyclophilin D exhibits tissue-specific control of metabolic homeostasis. PLoS One. 2016;11:e0167910. doi:10.1371/journal.pone.0167910

Javadov S, Jang S, Parodi-Rullán R, Khuchua Z, Kuznetsov AV. Mitochondrial permeability transition in cardiac ischemia-reperfusion: whether cyclophilin D is a viable target for cardioprotection? Cell Mol Life Sci. 2017;74:2795-2813. doi:10.1007/s00018-017-2502-4

Panel M, Ahmed-Belkacem A, Ruiz I, et al. A phenyl pyrrolidine derivative reveals a dual inhibition mechanism of myocardial mitochondrial permeability transition pore, which is limited by its myocardial distribution. J Pharmacol Exp Ther. 2020;376:348-357. doi:10.1124/jpet.120.000359

Grädler U, Schwarz D, Blaesse M, et al. Discovery of novel cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies. Bioorg Med Chem Lett. 2019;29:126717. doi:10.1016/j.bmcl.2019.126717

De Simone A, Georgiou C, Ioannidis H, et al. A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors. Chem Sci. 2019;10:542-547. doi:10.1039/c8sc03831g

Gutiérrez-Aguilar M, Baines CP. Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta. 2015;1850:2041-2047. doi:10.1016/j.bbagen.2014.11.009

Kofron JL, Kuzmic P, Kishore V, Colon-Bonilla E, Rich DH. Determination of kinetic constants for peptidyl prolyl cis-trans isomerases by an improved spectrophotometric assay. Biochemistry. 1991;30:6127-6134. doi:10.1021/bi00239a007

Walkinshaw MD, Taylor P, Turner NJ, Flitsch SL. Cyclophilin-binding ligands, WO048178A2, 2002. Accessed November 9, 2020. https://patents.google.com/patent/WO2002048178A2/en

Guo H, Wang F, Yu K, et al. Novel cyclophilin D inhibitors derived from quinoxaline exhibit highly inhibitory activity against rat mitochondrial swelling and Ca2+ uptake/release. Acta Pharmacol Sin. 2005;26:1201-1211. doi:10.1111/j.1745-7254.2005.00189.x

Mori T, Itami S, Yanagi T, Tatara Y, Takamiya M, Uchida T. Use of a real-time fluorescence monitoring system for high-throughput screening for prolyl isomerase inhibitors. J Biomol Screen. 2009;14:419-424. doi:10.1177/1087057109333979

Vivoli M, Renou J, Chevalier A, et al. A miniaturized peptidyl-prolyl isomerase enzyme assay. Anal Biochem. 2017;536:59-68. doi:10.1016/j.ab.2017.08.004

Caporale A, Mascanzoni F, Farina B, et al. FRET-protease-coupled peptidyl-prolyl cis-trans isomerase assay: new internally quenched fluorogenic substrates for high-throughput screening. J Biomol Screen. 2016;21:701-712. doi:10.1177/1087057116650402

Zemanova L, Vaskova M, Schmidt M, et al. RNase T1 refolding assay for determining mitochondrial cyclophilin D activity: a novel in vitro method applicable in drug research and discovery. Biochemistry. 2020;59:1680-1687. doi:10.1021/acs.biochem.9b01025

Park I, Londhe AM, Lim JW, et al. Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Aβ-induced mitochondrial dysfunction. J Comput Aided Mol Des. 2017;31:929-941. doi:10.1007/s10822-017-0067-9

Liu Y, Jiang J, Richardson PL, Reddy RD, Johnson DD, Kati WM. A fluorescence polarization-based assay for peptidyl prolyl cis/trans isomerase cyclophilin A. Anal Biochem. 2006;356:100-107. doi:10.1016/j.ab.2006.04.040

Sivandzade F, Bhalerao A, Cucullo L. Analysis of the mitochondrial membrane potential using the cationic JC-1 dye as a sensitive fluorescent probe. Bio Protoc. 2019;9:e3128.

Li W, Zhang C, Sun X. Mitochondrial Ca2+ retention capacity assay and Ca2+-triggered mitochondrial swelling assay. J Vis Exp. 2018;135:e56236. doi:10.3791/56236

Fancelli D, Abate A, Amici R, et al. Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo. J Med Chem. 2014;57:5333-5347. doi:10.1021/jm500547c

Roy S, Šileikytė J, Schiavone M, et al. Discovery, synthesis, and optimization of diarylisoxazole-3-carboxamides as potent inhibitors of the mitochondrial permeability transition pore. ChemMedChem. 2015;10:1655-1671. doi:10.1002/cmdc.201500284

Roy S, Šileikytė J, Neuenswander B, et al. N-phenylbenzamides as potent inhibitors of the mitochondrial permeability transition pore. ChemMedChem. 2016;11:283-288. doi:10.1002/cmdc.201500545

Kim J, Lee J, Moon B, et al. Pyridyl-urea derivatives as blockers of Aβ-induced mPTP opening for Alzheimer's disease. Bull Korean Chem Soc. 2012;33:3887-3888. doi:10.5012/bkcs.2012.33.11.3887

Kim YS, hwa Jung S, Park BG, et al. Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction. Eur J Med Chem. 2013;62:71-83. doi:10.1016/j.ejmech.2012.12.033

Jung Sh, Choi K, Pae AN, et al. Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers. Org Biomol Chem. 2014;12:9674-9682. doi:10.1039/C4OB01967A

Elkamhawy A, Lee J, Park BG, Park I, Pae AN, Roh EJ. Novel quinazoline-urea analogues as modulators for Aβ-induced mitochondrial dysfunction: design, synthesis, and molecular docking study. Eur J Med Chem. 2014;84:466-475. doi:10.1016/j.ejmech.2014.07.027

Park J, Elkamhawy A, Hassan AHE, et al. Synthesis and evaluation of new pyridyl/pyrazinyl thiourea derivatives: neuroprotection against amyloid-β-induced toxicity. Eur J Med Chem. 2017;141:322-334. doi:10.1016/j.ejmech.2017.09.043

Elkamhawy A, Park JE, Hassan AHE, et al. Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea: a new modulator for amyloid beta-induced mitochondrial dysfunction. Eur J Med Chem. 2017;128:56-69. doi:10.1016/j.ejmech.2016.12.057

Elkamhawy A, Park J, Hassan AHE, et al. Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of Aβ-induced mitochondrial dysfunction in Alzheimer's disease. Eur J Med Chem. 2018;144:529-543. doi:10.1016/j.ejmech.2017.12.045

Elkamhawy A, Park J, Hassan AHE, et al. Pyrazinyl ureas revisited: 1-(3-(Benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea, a new blocker of Aβ-induced mPTP opening for Alzheimer's disease. Eur J Med Chem. 2018;157:268-278. doi:10.1016/j.ejmech.2018.07.068

Murasawa S, Iuchi K, Sato S, et al. Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene. Bioorg Med Chem. 2012;20:6384-6393. doi:10.1016/j.bmc.2012.08.062

Waldmeier P, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters J. Cyclophilin D as a drug target. Curr Med Chem. 2003;10:1485-1506. doi:10.2174/0929867033457160

Kajitani K, Fujihashi M, Kobayashi Y, Shimizu S, Tsujimoto Y, Miki K. Crystal structure of human cyclophilin D in complex with its inhibitor, cyclosporin A at 0.96-A resolution. Proteins. 2008;70:1635-1639. doi:10.1002/prot.21855

Italia JL, Bhardwaj V, Kumar MNV Ravi. Disease, destination, dose and delivery aspects of ciclosporin: the state of the art. Drug Discov Today. 2006;11:846-854. doi:10.1016/j.drudis.2006.07.015

Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807-815. doi:10.1016/0092-8674(91)90124-h

Azzi JR, Sayegh MH, Mallat SG. Calcineurin inhibitors: 40 years later, can't live without. J Immunol. 2013;191:5785-5791. doi:10.4049/jimmunol.1390055

Cormack S, Mohammed A, Panahi P, et al. Effect of ciclosporin on safety, lymphocyte kinetics and left ventricular remodelling in acute myocardial infarction. Br J Clin Pharmacol. 2020;86:1387-1397. doi:10.1111/bcp.14252

Liddicoat AM, Lavelle EC. Modulation of innate immunity by cyclosporine A. Biochem Pharmacol. 2019;163:472-480. doi:10.1016/j.bcp.2019.03.022

Hansson MJ, Mattiasson G, Månsson R, et al. The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr. 2004;36:407-413. doi:10.1023/B:JOBB.0000041776.31885.45

Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol. 2002;62:22-29. doi:10.1124/mol.62.1.22

Bernardi P, Broekemeier KM, Pfeiffer DR. Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane. J Bioenerg Biomembr. 1994;26:509-517. doi:10.1007/BF00762735

Galat A, Metcalfe SM. Peptidylproline cis/trans isomerases. Prog Biophys Mol Biol. 1995;63:67-118. doi:10.1016/0079-6107(94)00009-x

Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem. 2002;277:34793-34799. doi:10.1074/jbc.M202191200

Gregory MA, Bobardt M, Obeid S, et al. Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family. Antimicrob Agents Chemother. 2011;55:1975-1981. doi:10.1128/AAC.01627-10

Moss SJ, Bobardt M, Leyssen P, et al. Sangamides, a new class of cyclophilin-inhibiting host-targeted antivirals for treatment of HCV infection. MedChemComm. 2012;3:944-949. doi:10.1039/C1MD00227A

Steadman VA, Pettit SB, Poullennec KG, et al. Discovery of potent cyclophilin inhibitors based on the structural simplification of sanglifehrin A. J Med Chem. 2017;60:1000-1017. doi:10.1021/acs.jmedchem.6b01329

Mackman RL, Steadman VA, Dean DK, et al. Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycle. J Med Chem. 2018;61:9473-9499. doi:10.1021/acs.jmedchem.8b00802

Azzolin L, Antolini N, Calderan A, et al. Antamanide, a derivative of amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition pore. PLoS One. 2011;6:e16280. doi:10.1371/journal.pone.0016280

Guichou JF, Colliandre L, Ahmed-Belkacem H, Pawlotsky JM. New inhibitors of cyclophilins and uses thereof, WO2011076784. 2011. Accessed July 1, 2020. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011076784

Guichou JF, Lionel C, Hakim A, Jean-Michel P. New inhibitors of cyclophilins and uses thereof, US 2013/0018044 A1, 2010. Acceseed July 6, 2019. https://lens.org/186-168-265-674-081

Guichou JF, Viaud J, Mettling C, Subra G, Lin YL, Chavanieu A. Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A. J Med Chem. 2006;49:900-910. doi:10.1021/jm050716a

Schrödinger Release 2020-4: Maestro. Schrödinger, LLC; 2020.

Thomson I, Shepherd RM, Fraser R, Kenyon CJ. Dantrolene inhibits adrenal steroidogenesis by a mechanism independent of effects on stored calcium release. J Steroid Biochem Mol Biol. 1991;38:703-707. doi:10.1016/0960-0760(91)90081-F

Chen S, Zhao X, Tan J, et al. Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity. Eur J Pharmacol. 2007;565:54-59. doi:10.1016/j.ejphar.2007.03.023

Valasani KR, Vangavaragu JR, Day VW, Yan SS. Structure based design, synthesis, pharmacophore modeling, virtual screening, and molecular docking studies for identification of novel cyclophilin D inhibitors. J Chem Inf Model. 2014;54:902-912. doi:10.1021/ci5000196

Kapetanovic IM. Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach. Chem Biol Interact. 2008;171:165-176. doi:10.1016/j.cbi.2006.12.006

Zheng H, Hou J, Zimmerman MD, Wlodawer A, Minor W. The future of crystallography in drug discovery. Expert Opin Drug Discov. 2014;9:125-137. doi:10.1517/17460441.2014.872623

Maveyraud L, Mourey L. Protein X-ray crystallography and drug discovery. Molecules. 2020;25:1030. doi:10.3390/molecules25051030

Neuroprotective Effect of 2-(Benzyloxy)arylureas Is Not Related to CypD Inhibition nor Suppression of mPTP Opening

The Mitochondrial Permeability Transition Pore-Current Knowledge of Its Structure, Function, and Regulation, and Optimized Methods for Evaluating Its Functional State