Is MDMX the better target?

Kon, Ning; Gu, Wei

doi:10.18632/aging.101479

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2019

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“…The usage of Mdm2 inhibitors in some cases is significantly limited due to its toxicity in normal cells [29]. Recently, it was reported that the loss of Mdmx induces p53 activation but has much less destructive effects in vivo than Mdm2 inhibition [30]. Therefore, Mdmx remains an interesting and unexplored target of great potential for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Focused Library Generator: case of Mdmx inhibitors

Xia

Karpov

Popowicz

et al. 2019

J Comput Aided Mol Des

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We present a Focused Library Generator that is able to create from scratch new molecules with desired properties. After training the Generator on the ChEMBL database, transfer learning was used to switch the generator to producing new Mdmx inhibitors that are a promising class of anticancer drugs. Lilly medicinal chemistry filters, molecular docking, and a QSAR IC 50 model were used to refine the output of the Generator. Pharmacophore screening and molecular dynamics (MD) simulations were then used to further select putative ligands. Finally, we identified five promising hits with equivalent or even better predicted binding free energies and IC 50 values than known Mdmx inhibitors. The

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Section: Introductionmentioning

confidence: 99%