Minimal Pharmacophoric Elements and Fragment Hopping, an Approach Directed at Molecular Diversity and Isozyme Selectivity. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors

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• 作者：Haitao Ji ; Benjamin Z. Stanton ; Jotaro Igarashi ; Huiying Li ; Pavel Martá ; sek ; Linda J. Roman ; Thomas L. Poulos ; Richard B. Silverman
• 刊名：Journal of the American Chemical Society
• 出版年：2008
• 出版时间：March 26, 2008
• 年：2008
• 卷：130
• 期：12
• 页码：3900 - 3914
• 全文大小：641K
• 年卷期：v.130,no.12(March 26, 2008)
• ISSN：1520-5126

文摘

Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing onligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of theminimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozymeselectivity are considered in deriving the minimal pharmacophoric elements. Five general-purpose librariesare established: the basic fragment library, the bioisostere library, the rules for metabolic stability, thetoxicophore library, and the side chain library. These libraries are employed to generate focused fragmentlibraries to match the minimal pharmacophoric elements for each pharmacophore and then to link thefragment to the desired molecule. This method was successfully applied to neuronal nitric oxide synthase(nNOS), which is implicated in stroke and neurodegenerative diseases. Starting with the nitroarginine-containing dipeptide inhibitors we developed previously, a small organic molecule with a totally differentchemical structure was designed, which showed nanomolar nNOS inhibitory potency and more than 1000-fold nNOS selectivity. The crystallographic analysis confirms that the small organic molecule with aconstrained conformation can exactly mimic the mode of action of the dipeptide nNOS inhibitors. Therefore,a new peptidomimetic strategy, referred to as fragment hopping, which creates small organic moleculesthat mimic the biological function of peptides by a pharmacophore-driven strategy for fragment-based denovo design, has been established as a new type of fragment-based inhibitor design. As an open system,the newly established approach efficiently incorporates the concept of early "ADME/Tox" considerationsand provides a basic platform for medicinal chemistry-driven efforts.