The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme.

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Tzakos AG, Naqvi N, Comporozos K, Pierattelli R, Theodorou V, Husain A, Gerothanassis IP

The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme.

Bioorg Med Chem Lett. 2006 Oct 1;16(19):5084-7. Epub 2006 Aug 2.

PubMed ID

16889963 [ View in PubMed

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Abstract

Enzyme-inhibitor recognition is considered one of the most fundamental aspects in the area of drug discovery. However, the molecular mechanism of this recognition process (induced fit or prebinding and adaptive selection among multiple conformers) in several cases remains unexplored. In order to shed light toward this step of the recognition process in the case of human angiotensin I converting enzyme (hACE) and its inhibitor captopril, we have established a novel combinatorial approach exploiting solution NMR, flexible docking calculations, mutagenesis, and enzymatic studies. We provide evidence that an equimolar ratio of the cis and trans states of captopril exists in solution and that the enzyme selects only the trans state of the inhibitor that presents architectural and stereoelectronic complementarity with its substrate binding groove.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Captopril	Angiotensin-converting enzyme	Protein	Humans	Yes	Inhibitor	Details