The relationship of rotatable bond count (N(rot)) and polar surface area (PSA) with oral bioavailability in rats was examined for 434 Pharmacia compounds and compared with an earlier report from Veber et al. (J. Med. Chem. 2002, 45, 2615). N(rot) and PSA were calculated with QikProp or Cerius2. The resulting correlations depended on the calculation method and the therapeutic class within the data superset. These results underscore that such generalizations must be used with caution.

K4 1992, 114, 9197-9198 f 9197 I [MoOSI2+ complexes is highly desirable.Stabilization of enzymatic [MoOSI2+ centers through an active site interaction, possibly with cysteine sulfur or molybdopterin, provides an attractive reconciliation of the extreme reactivity of such groups and their presence in nature. A potential interaction between the [MoOSIZ+ center and the dithiolene moiety of Mo-co is reflected in recently reported ene-l -perthiolate-2-thiolatemolybdenum(1V) complexes. 15b We have demonstrated that the stabilization of a [MoOSI2+ fragment by a sulfur-sulfur interaction only slightly perturbs the Mo=S bond; it is especially significant that the Mo-S( 1) distance in 3 falls within the range of M d distances found in molybdoenzymes and that this range, in turn, does not extend into that established crystallographically for cis-oxothic-or monothio-molybdenum complexes.10*21 Given an O = M d -. X fragment in the active site, it would be possible to account for other enzyme behavior by postulating the severing of the S-X interaction upon reduction or initiation of catalysis (through population of Mo=S A* to produce a nucleophilic S center). Finally, 3 reacts quantitatively with cyanide to produce 1 and SCN-via a short-lived intermediate; in the presence of water and oxygen this reaction yields 2 in a process which mimics the deactivation of xanthine oxidase upon cyanolysis.22Supplementary Material Available: Tables of positional parameters, anisotropic thermal parameters, bond distances, and bond angles for 3 (3 pages); tables of observed and calculated structure factors for 3 (7 pages). Ordering information is given on any current masthead page. (21) (a) Muller, A.; Diemann, E.; Jostes, R.; Bogge, H. Angew. Chem., Inr. Ed. Engl. 1981, 20, 934. (b) Bristow, S.; Collison, D.; Garner, C. D.; Clegg, W.

Template-directed polymerization reactions enable the accurate storage and processing of nature's biopolymer information. This mutualistic relationship of nucleic acids and proteins, a network known as life's central dogma, is now marvellously complex, and the progressive steps necessary for creating the initial sequence and chain-length-specific polymer templates are lost to time. Here we design and construct dynamic polymerization networks that exploit metastable prion cross-β phases. Mixed-phase environments have been used for constructing synthetic polymers, but these dynamic phases emerge naturally from the growing peptide oligomers and create environments suitable both to nucleate assembly and select for ordered templates. The resulting templates direct the amplification of a phase containing only chain-length-specific peptide-like oligomers. Such multi-phase biopolymer dynamics reveal pathways for the emergence, self-selection and amplification of chain-length- and possibly sequence-specific biopolymers.

Within drug discovery, it is desirable to determine whether a compound will penetrate and distribute within the central nervous system (CNS) with the requisite pharmacokinetic and pharmacodynamic performance required for a CNS target or if it will be excluded from the CNS, wherein potential toxicities would mitigate its applicability. A variety of in vivo and in vitro methods for assessing CNS penetration have therefore been developed and applied to advancing drug candidates with the desired properties. In silico methods to predict CNS penetration from chemical structures have been developed to address virtual screening and prospective design. In silico predictive methods are impacted by the quality, quantity, sources, and generation of the measured data available for model development. Key considerations for predictions of CNS penetration include the comparison of local (in chemistry space) versus global (more structurally diverse) models and where in the drug discovery process such models may be best deployed. Preference should also be given to in vitro and in vivo measurements of greater mechanistic clarity that better support the development of structure-property relationships. Although there are numerous statistical methods that have been brought to bear on the prediction of CNS penetration, a greater concern is that such models are appropriate for the quality of measured data available and are statistically validated. In addition, the assessment of prediction uncertainty and relevance of predictive models to structures of interest are critical. This article will address these key considerations for the development and application of in silico methods in drug discovery.The main interfaces between the central nervous system (CNS) and the peripheral circulation are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The surface area of the former (approximately 20 m 2 ) is several thousand times larger than the latter; thus, the BBB represents the most important barrier between the CNS and the systemic circulation (Pardridge, 2002;Graff and Pollack, 2004). There are at least two aspects of the BBB that make it a formidable barrier to candidate CNS drugs. First, in terms of its morphology, the endothelial cells of which the BBB is composed are connected by complex tight junctions, which severely limit any paracellular transport. Furthermore, a minimal level of pinocytosis and lack of significant membrane fenestrae affords an additional hindrance to the transport of hydrophilic molecules. Second, the BBB includes an array of metabolic enzyme systems and efflux transporters that constitutes a biochemical barrier to the majority of xenobiotics (de Boer et al., 2003). This combination of physical and biochemical barriers establishes the BBB endothelium as quite distinct from other endothelia, and it has been estimated to prevent the brain uptake of more than 98% of potential neurotherapeutics (Pardridge, 2002).