3B3N

Structure of neuronal NOS heme domain in complex with a inhibitor (+-)-N1-{cis-4'-[(6"-aminopyridin-2"-yl)methyl]pyrrolidin-3'-yl}ethane-1,2-diamine

Summary for 3B3N

• Entry DOI: 10.2210/pdb3b3n/pdb
• Related: 3B3M 3B3O 3B3P
• Descriptor: Nitric-oxide synthase, ACETATE ION, ZINC ION, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, heme enzyme, inhibitor, alternative splicing, calmodulin-binding, cell projection, fad, fmn, iron, membrane, metal-binding, nadp, oxidoreductase
• Biological source: Rattus norvegicus (Rat)
• Cellular location: Cell membrane, sarcolemma; Peripheral membrane protein (By similarity): P29476
• Total number of polymer chains: 2
• Total formula weight: 99994.68

Authors

Igarashi, J.,Li, H.,Poulos, T.L. (deposition date: 2007-10-22, release date: 2008-07-15, Last modification date: 2024-02-21)

Primary citation

Ji, H.,Stanton, B.Z.,Igarashi, J.,Li, H.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors.
J.Am.Chem.Soc., 130:3900-3914, 2008

PubMed Abstract: Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing on ligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of the minimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozyme selectivity are considered in deriving the minimal pharmacophoric elements. Five general-purpose libraries are established: the basic fragment library, the bioisostere library, the rules for metabolic stability, the toxicophore library, and the side chain library. These libraries are employed to generate focused fragment libraries to match the minimal pharmacophoric elements for each pharmacophore and then to link the fragment 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 different chemical 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 a constrained 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 molecules that mimic the biological function of peptides by a pharmacophore-driven strategy for fragment-based de novo 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" considerations and provides a basic platform for medicinal chemistry-driven efforts.

PubMed: 18321097
DOI: 10.1021/ja0772041

Experimental method

X-RAY DIFFRACTION (1.98 Å)