Alan Tinker

Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase

Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low levels, and a defensive cytotoxin at higher levels. The high active-site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock, and cancer. Our structural and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a novel specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents towards remote specificity pockets, accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active-site conservation.

Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?

Nitric Oxide (NO) is widely recognized as an important messenger and effector molecule in a variety of biological systems. There is strong evidence from animal models that elevated or lowered NO levels are associated with a variety of pathological states. In nature, NO is synthesised from the amino acid l-arginine by a small family of closely related oxygenase enzymes: the nitric oxide synthases (NOS). A number of studies in animals have associated excessive NO production by one of these enzymes--the inducible NOS isoform (iNOS or NOS-II)--with acute and chronic inflammation in model systems and have also demonstrated that administration of NOS inhibitors can produce beneficial effects. Regrettably, however, the relatively poor potency, selectivity and pharmacokinetic (ADME) profiles of the available inhibitors have so far precluded a convincing demonstration of their efficacy in the clinic. This review will describe the current state of knowledge of the structure and function of NOS and the various approaches that are being followed in the search for truly selective NOS inhibitors as therapeutic agents for inflammatory diseases.

A novel, base-induced fragmentation of hantzsch-type 4-aryl-1,4-dihydropyridines

Hantzsch-type 1,4-dihydropyridine derivatives substituted with highly electron-deficient aryl groups in the 4-position, on treatment with a variety of basic reagents in non-hydroxylic solvents, undergo an unexpected and ready scission of the inter-ring bond to give the corresponding 4-unsubstituted pyridine and an arene derived from the original 4-substituent. The scope of the reaction has been investigated and possible mechanisms are discussed.

Synthesis of phosphonates: a modified arbuzov procedure

Reactions of 6-iodogalactosides with either methyl or isopropyl diphenyl phosphite lead to diphenylphosphoryl derivatives; these can be converted by ester exchange into dibenzylphosphoryl derivatives, which are convenient precursors of carbohydrate phosphonic acids.