AI and computational chemistry-accelerated development of an alotaketal analogue with conventional PKC selectivity
Jumpei Maki1, Asami Oshimura1, Chihiro Tsukano1
1Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan. tsukano.chihiro.2w@kyoto-u.ac.jp.
Abstract:
The protein kinase C (PKC) family consists of ten isozymes and is a potential target for treating cancer, Alzheimer's disease, and HIV infection. Since known natural PKC agonists have little selectivity among the PKC isozymes, a new scaffold is needed to develop PKC ligands with remarkable isozyme selectivity. Taking advantage of machine-learning and computational chemistry approaches, we screened the PubChem database to select sesterterpenoids alotaketals as potential PKC ligands, then designed and synthesized alotaketal analogues with a different ring system and stereochemistry from the natural products. The analogue exhibited a one-order higher affinity for PKCα-C1A than for the PKCδ-C1B domain. Thus, this compound is expected to serve as the basis for developing PKC ligands with isozyme selectivity.
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