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Clinical Pharmacology & Biopharmaceutics | ISSN : 2167-065X
Volume 7
September 18-19, 2018 | Amsterdam, Netherlands
6
th
European Biopharma Congress
Euro Biopharma 2018
Finding pharmaceutical agents by assembling chemotypes
Jun Xu, Mengyang Xu, Liangyue Wang, Chao Zhao and He Peng
Sun Yat-sen University, China
T
his talk introduces
a de novo
chemotype (substructure) generation algorithm (DSGA) that derives frequent substructures in order
to avoid the subjectivity of empirical method, and avoid the meaningless substructures generated from algorithmic approaches by
statistical analyses. DSGA derives frequent chemical substructures (FCS) from a large compound library. In an FCS, substructures are
not inter-included. When the library is big enough to represent the chemical diversity, such as ZINC database (27 million medicinal
compounds), the resulting FCS is termed as the FCS dictionary (FCSD) for drug-like compounds. For a focused compound library (FL),
DSGA can derive a focused FCS (fFCS) from FL. (fFCS) can be used as structural descriptors for focus library SAR studies. Six focused
libraries against targets PDE4D, mTOR, HDAC1, DPP4, BACE andALR2 were tested with DSGAapproach. Using the (fFCS) as structural
descriptor sets, six virtual screening models were generated to predict ligands against the targets; the prediction accuracies are greater than
90%. Three methods were proposed to assembly drug-like molecules from substructures: Using the laws in the nature, such as isoprene
rule; organic synthesis rules, such as retro-synthon rules proposed by E J Corey; pharmaceutical rules derived from a focused compound
library against a specific target. We use DSGA to figure out rules that are used to compose privileged scaffolds by assembling FCS. It can
be chemically challenging to make the compounds proposed by these assembling approaches. By combining DSGAmethod, bioisosterism
method and click chemistry, we generated privileged chemome (substructures/chemotypes) from Hsp90 inhibitor library, and then found
out available chemical fragments with bioisosterism rules. With SPR technology, we confirmed the fragments that interacted with Hsp90.
Finally, we used “click chemistry” to assemble the substructures and produced nanomolar selective Hsp90 inhibitors.
junxu@biochemomes.comClin Pharmacol Biopharm 2018, Volume:7
DOI: 10.4172/2167-065X-C1-029