000117621 001__ 117621
000117621 005__ 20240319081006.0
000117621 0247_ $$2doi$$a10.3390/ijms23094502
000117621 0248_ $$2sideral$$a129167
000117621 037__ $$aART-2022-129167
000117621 041__ $$aeng
000117621 100__ $$0(orcid)0000-0003-4358-9110$$aConde-Giménez, M.
000117621 245__ $$aAlchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase
000117621 260__ $$c2022
000117621 5060_ $$aAccess copy available to the general public$$fUnrestricted
000117621 5203_ $$aPhenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ¿¿Gb values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
000117621 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E45-20R$$9info:eu-repo/grantAgreement/ES/DGA/LMP30-18$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P$$9info:eu-repo/grantAgreement/ES/MINECO/PID2019- 107293GB-I00
000117621 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000117621 590__ $$a5.6$$b2022
000117621 592__ $$a1.154$$b2022
000117621 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b66 / 285 = 0.232$$c2022$$dQ1$$eT1
000117621 593__ $$aMedicine (miscellaneous)$$c2022$$dQ1
000117621 591__ $$aCHEMISTRY, MULTIDISCIPLINARY$$b52 / 178 = 0.292$$c2022$$dQ2$$eT1
000117621 593__ $$aPhysical and Theoretical Chemistry$$c2022$$dQ1
000117621 593__ $$aComputer Science Applications$$c2022$$dQ1
000117621 593__ $$aInorganic Chemistry$$c2022$$dQ1
000117621 593__ $$aSpectroscopy$$c2022$$dQ1
000117621 593__ $$aOrganic Chemistry$$c2022$$dQ1
000117621 593__ $$aMolecular Biology$$c2022$$dQ2
000117621 593__ $$aCatalysis$$c2022$$dQ2
000117621 594__ $$a7.8$$b2022
000117621 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000117621 700__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos, J. J.$$uUniversidad de Zaragoza
000117621 700__ $$0(orcid)0000-0002-2043-4864$$aGaliana-Cameo, M.$$uUniversidad de Zaragoza
000117621 700__ $$0(orcid)0000-0002-8839-6796$$aMahía Moros, A.
000117621 700__ $$aVictor, B. L.
000117621 700__ $$0(orcid)0000-0003-0195-5434$$aSalillas Berges, S.$$uUniversidad de Zaragoza
000117621 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, A.$$uUniversidad de Zaragoza
000117621 700__ $$aBrito, R. M. M.
000117621 700__ $$0(orcid)0000-0002-4972-7476$$aGálvez Lafuente, J. A.$$uUniversidad de Zaragoza
000117621 700__ $$0(orcid)0000-0001-9033-8459$$aDíaz-de-villegas, M. D.
000117621 700__ $$0(orcid)0000-0002-2879-9200$$aSancho Sanz, J.$$uUniversidad de Zaragoza
000117621 7102_ $$12010$$2760$$aUniversidad de Zaragoza$$bDpto. Química Inorgánica$$cÁrea Química Inorgánica
000117621 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000117621 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDpto. Química Orgánica$$cÁrea Química Orgánica
000117621 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000117621 773__ $$g23, 9 (2022), 4502 [21 pp]$$pInt. j. mol. sci.$$tInternational Journal of Molecular Sciences$$x1661-6596
000117621 8564_ $$s8421771$$uhttps://zaguan.unizar.es/record/117621/files/texto_completo.pdf$$yVersión publicada
000117621 8564_ $$s2806718$$uhttps://zaguan.unizar.es/record/117621/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
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000117621 951__ $$a2024-03-18-14:36:47
000117621 980__ $$aARTICLE