Background: The complexity of the problem of the origin of life has spawned a large number of possible evolutionary scenarios. Their number, however, can be dramatically reduced by the simultaneous consideration of various bioenergetic, physical, and geological constraints.
Abstract:The acid-base dissociation constant (pK a ) of a drug is a key physicochemical parameter infl uencing many biopharmaceutical characteristics. While this has been well established, the overall proportion of non-ionizable and ionizable compounds for drug-like substances is not well known. Even less well known is the overall distribution of acid and base pK a values. The current study has reviewed the literature with regard to both the proportion of ionizable substances and pK a distributions. Further to this a set of 582 drugs with associated pK a data was thoroughly examined to provide a representative set of observations. This was further enhanced by delineating the compounds into CNS and non-CNS drugs to investigate where differences exist. Interestingly, the distribution of pK a values for single acids differed remarkably between CNS and non-CNS substances with only one CNS compound having an acid pK a below 6.1. The distribution of basic substances in the CNS set also showed a marked cut off with no compounds having a pK a above 10.5. The pK a distributions of drugs are infl uenced by two main drivers. The fi rst is related to the nature and frequency of occurrence of the functional groups that are commonly observed in pharmaceuticals and the typical range of pK a values they span. The other factor concerns the biological targets these compounds are designed to hit. For example, many CNS targets are based on seven transmembrane G protein-coupled receptors (7TM GPCR) which have a key aspartic acid residue known to interact with most ligands. As a consequence, amines are mostly present in the ligands that target 7TM GPCR's and this infl uences the pK a profi le of drugs containing basic groups. For larger screening collections of compounds, synthetic chemistry and the working practices of the chemists themselves can infl uence the proportion of ionizable compounds and consequent pK a distributions. The fi ndings from this study expand on current wisdom in pK a research and have implications for discovery research with regard to the composition of corporate databases and collections of screening compounds. Rough guidelines have been suggested for the profi le of compound collections and will evolve as this research area is expanded.
Transient-electric-birefringence experiments were conducted on four samples of hyaluronic acid over the molecular-mass (M) range 5 x 10-4 x 106 in dilute aqueous solution. The geometrical, optical and electrical characteristics were monitored via the rotary relaxation times, optical-polarizability antisotropies and electrical polarizabilities respectively. Each indicates the molecular conformation to be consistent with some degree of rigidity at low M but that this does not persist at high M. The molecules do not become true random coils, but are best characterized in terms of a persistence length of 20nm or 20 disaccharide units.
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