The integration of high throughput technologies for drug discovery.

Producing quality clinical candidates less prone to late stage failure is greatly facilitated by better integration of the relevant high throughput functions and the inclusion of ADME/toxicology further upstream in the discovery process. We describe the tasks and their integration in the context of the design, make and test triad.

Applications of random sampling to virtual screening of combinatorial libraries.

We describe statistical techniques for effective evaluation of large virtual combinatorial libraries (> 10(10) potential compounds). The methods described are used for computationally evaluating templates (prioritization of candidate libraries for synthesis and screening) and for the design of individual combinatorial libraries (e.g., for a given diversity site, reagents can be selected based on the estimated frequency with which they appear in products that pass a computational filter). These statistical methods are powerful because they provide a simple way to estimate the properties of the overall library without explicitly enumerating all of the possible products. In addition, they are fast and simple, and the amount of sampling required to achieve a desired precision is calculable. In this article, we discuss the computational methods that allow random product selection from a combinatorial library and the statistics involved in estimating errors from quantities obtained from such samples. We then describe three examples: (1) an estimate of average molecular weight for the several billion possible products in a four-component Ugi reaction, a quantity that can be calculated exactly for comparison; (2) the prioritization of four templates for combinatorial synthesis using a computational filter based on four-point pharmacophores; and (3) selection of reagents for the four-component Ugi reaction based on their frequency of occurrence in products that pass a pharmacophore filter.

Curious structure in "canonical" alanine-based peptides.

We have performed all atom simulations of blocked peptides of the form (AAXAA)3, where X = Gln, Asn, Glu, Asp, Arg, and Lys with explicit water molecules to examine the interactions between side chains spaced i,i-5 in the sequence. Although side chains in this i,i-5 arrangement are commonly believed to be noninteracting, we have observed the formation of unusual i,i-5 main chain hydrogen bonding in such sequences with positively charged residues (Lys) as well as polar uncharged groups (Gln). Our results are consistent with the unusual percentage of hydrogen bonding curves produced by amide exchange measurements on the well-studied sequence acetyl-(AAQAA)3-amide in water (Shalongo, W., Dugad, L., Stellwagen, E. J. Am. Chem. Soc. 116:8288-8293, 1994). Analysis of our simulations indicated that the glutamine side chain showed the greatest propensity to support pi helix formation and that the i,i-5 intramolecular hydrogen bonds were stabilized by water-bridging side chain interactions. This intermittent formation of the unusual pi helix structure was observed for up to 23% of the total simulation time in some residues in (AAQAA)3. Control studies on peptides with glutamine side chains spaced i,i-3, i,i-4 and i,i-6 did not reveal similar unique structures, providing stronger evidence for the unique role side chain interactions with i,i-5 spacing.