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.

Physicochemical properties such as lipophilicity and molecular mass are known to have an important influence on the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of small-molecule drug candidates. To assess the use of this knowledge in reducing the likelihood of compound-related attrition, the molecular properties of compounds acting at specific drug targets described in patents from leading pharmaceutical companies during the 2000-2010 period were analysed. Over the past decade, there has been little overall change in properties that influence ADMET outcomes, but there are marked differences in molecular properties between organizations, which are maintained when the targets pursued are taken into account. The target-unbiased molecular property differences, which are attributable to divergent corporate drug design strategies, are comparable to the differences between the major drug target classes. On the basis of our analysis, we conclude that a substantial sector of the pharmaceutical industry has not modified its drug design practices and is still producing compounds with suboptimal physicochemical profiles.

Using databases of oral drugs and recent compounds from the patents of major pharmaceutical companies, trends in molecular properties over time are identified. It is shown that the physical property profiles of oral drugs are not absolute, but depend on both ion class and the time of the drug invention. Properties examined include lipophilicity, molecular weight, hydrogen bond donors and acceptors, polar surface area, aromaticity, chirality and tetrahedral (sp3) carbon atom count. Lipophilicity is increasing over time in oral drugs that are neutral or acidic, but not in basic drugs, and has been converging in all ion classes towards a common constant range since the 1960s. In contrast, molecular weight is increasing over time in all ion classes. Hydrogen bond donors (OH + NH group count) are stable over time but hydrogen bond acceptors (O + N atom count) are increasing over time. It is shown that measures using sp3 atom and aromatic atom counts are inversely related and a new parameter, Ar atom count -sp3 atom count (Ar-sp3), describing shape or aromatic/aliphatic balance, is introduced. Ar-sp3 is constant over time in oral drugs, but is higher in patented compounds, independently of molecular weight and lipophilicity. The ion classes in patent compounds occupy distinct molecular weight/lipophilicity/shape chemical space. These properties are significantly increased versus oral drugs, with the exception of the most recently discovered acidic drugs, and occur in most, but not all target classes. While ceilings for lipophilicity in acids and neutral compounds may not have been reached, the design of potential drug molecules with reduced ADMET risk is indicated by a seeking a better balance between lipophilicity, 3-dimensionality and aromaticity.