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Title: Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase
Authors: Conde-Giménez, María
Galano-Frutos, Juan José
Galiana-Cameo, María
Mahía, Alejandro
Victor, Bruno L. 
Salillas, Sandra
Velázquez-Campoy, Adrián
Brito, Rui M. M. 
Gálvez, José Antonio
Díaz-de-Villegas, María D.
Sancho, Javier
Keywords: phenylketonuria; pharmacological chaperones; lead optimization; alchemical free energy calculations; binding energetics
Issue Date: 19-Apr-2022
Project: MINECO, Spain, grants BFU2016-78232-P and PID2019- 107293GB-I00 
Gobierno de Aragón, Spain, grants LMP30_18 and E45_20R 
M.C.-G. was recipient of a predoctoral contract from Gobierno de Aragón, Spain 
Serial title, monograph or event: International Journal of Molecular Sciences
Volume: 23
Issue: 9
Abstract: Phenylketonuria (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 ΔΔGb 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.
ISSN: 1422-0067
DOI: 10.3390/ijms23094502
Rights: openAccess
Appears in Collections:FCTUC Química - Artigos em Revistas Internacionais

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