Process for the identification of a compound which inhibits the binding of the first bromodomain of each of human BRD-2, BRD-3, and BRD-4
Abstract:
A process for the identification of compounds with a molecular weight in the range 100 to 750 which inhibit the binding of the first and/or second bromodomains of human BRD-2 to 4 to acetylated lysine residues of their physiological partner proteins which comprises selecting those compounds which are able to: a) form a hydrogen bonding interaction in which the compound accepts a hydrogen bond from the sidechain NH2 group of the asparagine residue found at: BRD-2 BRD-2 BRD-3 BRD-3 BRD-4BRD-4 BD1BD2BD1BD2BD1BD2 ASN156ASN429ASN116ASN391ASN140ASN433 or b) accept a water-mediated hydrogen bond in which the compound accepts a hydrogen bond from a water that is itself hydrogen-bonded to the sidechain hydroxyl of the tyrosine residue found at BRD-2 BRD-2 BRD-3 BRD-3 BRD-4BRD-4 BD1BD2BD1BD2BD1BD2 TYR113TYR386TYR73TYR348TYR97TYR390 and c) which are also able to form a Van der Waals interaction with a lipophilic binding region of a binding pocket such that one or more heavy atoms of the said compounds lie within a 5 Å range of any of the heavy atoms of the following bromodomain residues which define the binding pocket: BRD-2 BRD-2 BRD-3 BRD-3 BRD-4BRD-4 BD1BD2BD1BD2BD1BD2 TRP97TRP370TRP57TRP332TRP81TRP374 PRO98PRO371PRO58PRO333PRO82PRO375 ASP161ASP434ASP121GLU396ASP145GLU438 ILE162VAL435ILE122VAL397ILE146VAL439 MET165MET438MET125MET400MET149MET442 pharmaceutical compositions containing such compounds, and their use in therapy.
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