Combi chem

Along with all the data generated by combi-chem and high-throughput screening (HTS) came the need to manage and analyze the data. Hence, computers and the science of informatics became increasingly vital. 

P. Zajdel, M. Pawlowski, J. Martinez, and G. Subra, Combi. Chem. High Through. Screen., 2009,12, 723. 

Linked drug-like scaffolds Combi-chem scaffolds Truncated lead compound... 

Lew, A., Krutzik, P.O., Hart, M.E. and Chamberlin, A.R., Increasing rates of reaction microwave-assisted organic synthesis for combinatorial chemistry, /. Combi. Chem., 2002, 4(2), 95-105. 

Lord. J., Routberg, M. and Sarko, C., High-throughput Microwave-Accelerated Combinatorial Chemistry A Plate-Based Approach, J. Combi. Chem. (submitted). 

Coleman, C.M., MacElroy, J.M.D., Gallagher, J.F. and O Shea, D.l F., Microwave parallel library generation comparison of a conventional- and microwave-generated substituted 4(5)-sulfanyl-lH-imidazole library, /. Combi. Chem., 2002, 4(1), 87-93. 

To match the incredible diversity of molecular space, pharmaceutical companies often rely on combinatorial chemistry. Combinatorial chemistry, or less formally combi chem or even just combi, is a technique for synthesizing large numbers of different molecules... 

Wagner DS, Markworth CJ, Wagner CD, Schoenen FJ, Rewerts CE, Kay BK, Geysen HM, Ratio encoding combinatorial libraries with stable isotopes and their utility in pharmaceutical research, Combi. Chem. High Throughput Screen, 1 143-153, 1998. 

Combinatorial chemistry (Combi Chem) Used to make thousands of variants of a compound. Consider a compound with a six-membered aromatic ring and a chlorine atom attached at a certain position. One might change the location of the chlorine to any of the other five positions, or change the chlorine to a fluorine or a bromine, and/or make the same changes at all the other five positions. To enumerate all the possible combinations is to make a combinatorial library. 

New Leads Generation (combi-chem/HTS) Drives a bipolar information engine... 

X. Chen, M. Liu, M. K. Gilson, J. Combi. Chem. High-Throughput Screen 2001, 4, 719-725, database can be found at http //www.bindingdb.org/ F. Horn,... 

Cesareni, G., CastagnoU, L. and Cestra, G., Combi. Chem. High Throughput Synth. 2, 1-17 (1999). 

DeSimone RW. The use of combi chem, high-speed analog chemistry and HTS in drug discovery. Drug Discov. Today 2003 8 156. For information on Hamamatsu FDSS. www.hamamtsu.com. 

Berger, T.A. Fogleman, K. Staats, T Bente, P Crocket, L Farrell, W. Osonubi, M. The Development of a Semi-preparatory Scale Supercritical-fluid Chromatograph for High-throughput Purification of Combi-Chem Libraries, J. Biochem. Biophys. Methods 43, 87-111 (2000). 

Davies K., Briant C., Network Science, http //www.netsci.org/Science/Combi-chem/feature05.html (1995). 

There is a universal desire in drug discovery to increase water solubility or, actually, to decrease hydrophobic ty. Many of the lead compounds produced, particularly by combi-chem, tend to be far too lipophylic. In fact, most small organic molecules are not very soluble in water. Nevertheless, many chemists think that because SFC mobile phases are nonaqueous, their compounds will not be soluble and SFC will not work for them. 

In high-throughput purification, HPLC-MS (and, increasingly, SFC-MS) is usually used to first screen all the samples. Lead generation techniques like combi-chem tend to be relatively inefficient in the automated synthesis of large number of different but related compounds. A private survey of numerous pharmaceutical companies concluded that it is typical to register only 50% of the compounds synthesized. There may be no product, or not enough product, or too many closely related compounds in any one reaction vessel. 

Figure 14 SFC-MS result from a combi-chem sample. Whereas the UV spectrum shows that multiple compounds are present, the mass spectrometer shows that only one of them has the correct mass. Waters ZQ with negative Ion APCI Interface used.

Berger TA, Fogelman K, Staats T, Bente P, Crocket I, Farrel W, Osonubi M. The development of a semi-preparatory scale supercritical-fluid chromatograph for high throughput purification of combi-chem libraries. J Biochem Biophys Methods 2000 43 87-111. 

---