Structural Characterization of the Human Androgen Receptor Ligand-binding Domain Complexed with EM5744, a Rationally Designed Steroidal Ligand Bearing a Bulky Chain Directed toward Helix 12

Antiandrogens are commonly used to treat androgen-dependent disorders. The currently used drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal antiandrogens. Our compounds are specially designed to impede repositioning of the mobile carboxyl-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned the of of thus for to of very affinity for very the of the the of the chain in the of the of a new that the affinity of the of chain to the repositioning of be to the of the the to steroidal antiandrogens. Antiandrogens are commonly used to treat androgen-dependent disorders. The currently used drugs unfortunately possess very weak affinity for the human AR (hAR), thus indicating the need to develop new high-affinity steroidal antiandrogens. Our compounds are specially designed to impede repositioning of the mobile carboxyl-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using crystal structures of the hARLBD, we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned the of of thus for to of very affinity for very the of the the of the chain in the of the of a new that the affinity of the of chain to the repositioning of be to the of the the to steroidal antiandrogens. The human used human ligand-binding ligand-binding human used human ligand-binding ligand-binding human a of the of possess a of a a a ligand-binding domain of to ligand-binding pocket that the of the carboxyl-terminal 12, located in the by to directly found in the of ligand-dependent transactivation function (AF-2) H12 repositioning of that the located in helix found in the The human AR thus to the the found in in the domain of domain to for androgen-dependent to be in a of androgen-dependent which the a of the of the the in the of androgen-dependent of thus by the of by to the compounds to the of to the in could be by the that the currently very affinity for the that of be in to be thus of to develop new affinity to the of to the the the of of the of new we to of the human a to the The to a a chain to ligand-binding by of the crystal structures of the ligand-binding domain in a a the the a in the transactivation domain (AF-2) by a of the of the from the chain from the H12 from the found in the a for the crystal structures of in the that H12 the that in the that helix for the function of the of in the in the by the of the in a from the the we to to the for a chain to the by the from a for the of the chain the of the affinity of compounds for to affinity that of in the of the compounds to the of to be a to be very of thus indicating that the of the chain of for the of the of we to a of compounds in the human ligand-binding we the crystal of of compounds to the hARLBD, a a affinity for the that of chain from from the of a of in The of the by to of a a of in of the by The to the a The in a for The a by to a in in of for in affinity of for the the in of human human of the of of to the by of of by a of The for of in in a of to to the of the for The the of compounds to be from in in the of to the of in the of to the The of to for of The by of in The in the a in for in the in a The a The affinity the a The a The to of of the of the The by a of in to of the hARLBD, in 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the H12 by in the thus that to of the of by the in the a of H12 to the from ligand-dependent transactivation function we the of directly in the the helix the of The of in a in which the of the to the by of which the of the of the structures that of are indicating the of by the chain of the very to of the crystal that for the of steroidal the that the chain the steroidal from the in a that very to that of in to affinity for the that the chain of compounds be to the the of to a a we that a chain the of a the in the to the that by H12 in the thus that chain could of of the of the the of the that could the of the of the that could new located in the of the Using new compounds be compounds a very affinity for the in of a chain a very affinity a could for new of steroidal new for of from compounds could be in to treat a of in the the could very to of compounds to to for of the for

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.