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Figure 2.
Binding pocket of Cyclopiazonic acid. A, topology of the CPA
binding site. Conjugated doublebond systems of the CPA molecule
are high lighted in green. Atom numbering in CPA is according to
International Union of Pure and Applied Chemistry (IUPAC)
nomenclature. B, fragment-based view of the CPA binding pocket.
The drug binding pocket can be subdivided into three regions,
each accommodating drug moieties of distinct chemical character.
The polar region (designated A, highlighted in yellow)
coordinates the acyl-tetramic acid moiety, with Gln^56, Asp^59,
and Asn^101 as main interacting residues. The coordinated M^2+
occupies a central position in this interaction. The center of
the pocket displays a preference for conjugated π-systems (B,
highlighted in blue). BHQ binds to this part, superposing with
CPA in this “B-pocket.” The relatively wide hydrophobic
region of the pocket (C, highlighted in green) accommodates
bulky, non-polar moieties. The decomposed analysis of this site
proposes functional extensions or modifications to yield
tailored high affinity drugs. For instance, an aliphatic chain
at site D, bridging toward the TG binding site, and a suitable
hydrogen-bonding partner to Asp^254 (region E), may further
improve drug affinity.
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