Design of inhibitors of scytalone dehydratase: probing interactions with an asparagine carboxamide.
Among the active-site residues of scytalone dehydratase, the side-chain carboxamide of asparagine 131 has the greatest potential for strong electrostatic interactions. Structure-based inhibitor design aimed at enhancing interactions with this residue led to the synthesis of a series of highly potent inhibitors that have a five- or six-membered ring containing a carbonyl functionality for hydrogen bonding. To achieve a good orientation for hydrogen bonding, the inhibitors incorporate a phenyl substituent that displaces a phenylalanine residue away from the five- or six-membered rings. Without the phenyl substituent, inhibitor binding potency is diminished by three orders of magnitude. Larger K(i) values of a site-directed mutant (Asn131Ala) of scytalone dehydratase in comparison to those of wild-type enzyme validate the design concept. The most potent inhibitor (K(i)=15 pM) contains a tetrahydrothiophenone that can form a single hydrogen bond with the asparagine carboxamide. Inhibitors with a butyrolactam that can form two hydrogen bonds with the asparagine carboxamide demonstrate excellent in vivo fungicidal activity.
Basarab
Gregory S
GS
DuPont Central Research & Development, Experimental Station, Wilmington, DE 19880, USA. greg.basarab@astrazeneca.com
Jordan
Douglas B
DB
Gehret
Troy C
TC
Schwartz
Rand S
RS
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001216:Asparagine / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors; D005659:Fungicides, Industrial / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D001216:Asparagine; D006836:Hydro-Lyases; C082741:scytalone dehydratase