Libraries fragment

The definition of fragment varies, but usually refers to molecules with a molecular weight less than 200-300 Daltons and consisting of fewer than 15-20 heavy atoms.9,10 A small ( 50 000 member) diverse library is generally sufficient for high throughput screening to yield a low affinity hit. 

This library consisted of molecules with an average molecular weight of 157.3 Daltons. 

4 Lipinski s Rule of Five for Orally Active Drugs 

The failure of drugs at later stages of development, particularly in clinical trials, is very expensive for drug developers and, more importantly, patients. To better understand the key reasons for these failures, Lipinski et al,14 undertook an analysis of the properties of compounds that entered Phase II human clinical trials. They selected a subset of 2245 compounds from the World Drug Index (WDI) database of over 50000 compounds after eliminating the majority of compounds for various well-reasoned criteria. This subset of compounds had assigned trade names and, as a result, were assumed to have entered Phase II oral efficacy studies and be expected to have superior physico-chemical properties since they would have passed most of the other earlier clinical trial hurdles. 

Compound solubility and permeability were identified as key factors in advancing these 2245 compounds into human trials. The authors compared the calculated properties of these compounds with the corresponding properties of the compounds of the entire database. Four parameters appeared to be correlated with solubility and permeability, namely molecular weight (MW), log P, 

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Fingerprints structural keys identify a molecule - code is highly compact represented in bits ambiguous not convertible to other representations dependent on the fragment library... 

Approximately 1,200 amines and 300 carboxylic acids were selected for inclusion in the fragment libraries, from which approximately 20 fragment libraries were synthesized. These libraries yielded 2,000 products with sufficient purity (>95%) and quantity (1.2 mL of 30 xM solution), and the product structures were confirmed via ID NMR. This fragment collection became known as the NMR Combicores to denote their purpose and their combichem origin. It was distributed across several major Pfizer research sites and used in multiple fragment screens. 

SeeDs-2 library was generated from their in-house database called rCat of 1,622,763 unique chemical compounds assembled from 23 suppliers (25). The filtering cascade began with MW (same as SeeDs-1), then the functional groups and solubility filters which resulted in 43 unique compounds (no overlap with SeeDs-1). These were then clustered by 2D, 3-point pharma-cophoric features to provide 3 clusters, and the centroids of each cluster was submitted for chemist review. Of the 395 selected compounds that were ordered, 357 passed QC to become the SeeDs-2 fragment library. 

The final library was designed with the purpose of adding incremental diversity to the first three fragment libraries. The main filtering criterion was novel pharmacophoric triangles not found in the first three libraries. After clustering and visual inspection from a panel of medicinal chemists, only 65 compounds were purchased and 61 compounds passed QC. 

Comparison of Hits, Nonhits, and the Entire Fragment Library... 

Overview of some key physical properties for selected fragment libraries and their associated screening methods... 

Chen, I., Hubbard, R. E. (2009) Lessons for fragment library design analysis of output from multiple screening campaigns. J Comput Aided Mol Des 23, 603-620. 

Brewer, M., Ichihara, O., Kirchhoff, C., Schade, M., Whittaker, M. (2008) Assembling a fragment library. Fragment-Based Drug Discovery A Practical Approach, in (Zartler, E., Shapiro, M. J. eds.), pp. 39-62. 

Bemis and Murcko (10) analyzed known drugs in an effort to identify common features and scaffolds, which could be used to bias fragment libraries toward drug-like structures. An optimal molecular complexity was also discussed by Hann and coworkers... 

If co-crystallization is indicated by properties of the protein or the fragment library, then prepare a solution of the protein with suitable concentration of fragment(s), (suggested 100 mM). Screen this solution around known crystallization conditions for the protein. If no crystals are observed a full screen using numerous conditions may be indicated. 

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