CCLab--a multi-objective genetic algorithm based combinatorial library design software and an application for histone deacetylase inhibitor design.

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Fang G, Xue M, Su M, Hu D, Li Y, Xiong B, Ma L, Meng T, Chen Y, Li J, Li J, Shen J

CCLab--a multi-objective genetic algorithm based combinatorial library design software and an application for histone deacetylase inhibitor design.

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4540-5. doi: 10.1016/j.bmcl.2012.05.123. Epub 2012 Jun 7.

PubMed ID
22738629 [ View in PubMed
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Abstract

The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5x6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20 mug/mL, with IC(50) values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)180N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)140N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)120N/AN/ADetails