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Message boards : News : New paper: Computational and experimental characterization of NF023, a candidate anticancer compound inhibiting…

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Toni
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Message 55233 - Posted: 2 Sep 2020 | 8:05:21 UTC


Here we studied a possible mode of action of NF023, a molecule which disrupts some protein-protein interactions (cIAP-TRAF) misregulated in cancer. The molecule is very charged and flexible, so classical docking studies aren't up to a full modeling... but large-scale MD powered by GPUGRID is.


Cossu F, Sorrentino L, Fagnani E, Zaffaroni M, Milani M, Giorgino T, Mastrangelo E. Computational and experimental characterization of NF023, a candidate anticancer compound inhibiting cIAP2/TRAF2 assembly. J Chem Inf Model. 2020 Aug 21 doi:10.1021/acs.jcim.0c00518



Protein-protein interactions are the basis of many important physiological processes, and are currently promising, yet difficult, targets for drug discovery. In this context, inhibitors of apoptosis (IAPs)-mediated interactions are pivotal for cancer cell survival; the interaction of the BIR1 domain of cIAP2 with TRAF2 was shown to lead the recruitment of cIAPs to the TNF-receptor, promoting the activation of NF-κB survival pathway. In this work, using a combined in silico-in vitro approach we identified a drug-like molecule, NF023, able to disrupt cIAP2 interaction with TRAF2. We demonstrated in vitro its ability to interfere with the assembly of the cIAP2-BIR1/TRAF2 complex and performed a thorough characterization of the compound’s mode of action through 248 parallel unbiased molecular dynamics simulations of 300 ns (totaling almost 75 µs of all-atom sampling), which identified multiple binding modes to the BIR1 domain of cIAP2 via clustering and ensemble docking. NF023 is, thus, a promising protein-protein interaction disruptor, representing a starting point to develop modulators of NF-κB-mediated cell survival in cancer. This study represents a model-procedure that shows the use of large-scale molecular dynamics methods to typify promiscuous interactors.

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Message 55236 - Posted: 2 Sep 2020 | 9:46:48 UTC - in response to Message 55233.

Nice!!

Always good to see results from the hard workng team at Gpugrid.

[CSF] Thomas H.V. Dupont
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Message 55240 - Posted: 2 Sep 2020 | 15:34:04 UTC - in response to Message 55236.

Nice!!

Always good to see results from the hard workng team at Gpugrid.

+1 :) Thanks Toni!
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Message 55241 - Posted: 2 Sep 2020 | 16:01:41 UTC - in response to Message 55240.

[quote]Nice!!

Always good to see results from the hard workng team at Gpugrid.

+1 :) Thanks Toni![/quote
+100

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Message 55262 - Posted: 6 Sep 2020 | 13:55:49 UTC
Last modified: 6 Sep 2020 | 13:59:11 UTC

I'm wondering why I'm not getting any of these in my "Scientific Publications"... all I have so far is "579th/672 Martinez-Rosell et al, JCIM 2020" but I've been in the top five by production since that paper, and newer ones I see in others' publications lists haven't appeared.

Just my usual luck I guess. :^)

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Message 55274 - Posted: 11 Sep 2020 | 11:18:38 UTC - in response to Message 55262.

The process between calculations and scientific publication is quite involved. The lag between getting results, analysis, authoring, iterating, submitting the paper, reviewing it, and so on may easily take years.

Also, some papers are based on relatively few WUs, so only a few random crunchers get them.

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Message 55275 - Posted: 11 Sep 2020 | 11:32:07 UTC - in response to Message 55274.

Thank you for the response! That answers it quite nicely. :^)

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Message boards : News : New paper: Computational and experimental characterization of NF023, a candidate anticancer compound inhibiting…