Molecular Dynamics and myeloma

The basic data manipulation tasks have been covered in the "Toenail Fungus" example so will not be repeated.

A range of stams were selected as targets to suppress myeloma.  This requires extensive searching of literature on Pubmed and continual reference to a good site that keeps up-to-date with advances in the disease of interest.  For myeloma the best I have found is The Myeloma Crowd .  We will only cover two examples here but the principle covers all such targets.

In the section about drugs I covered the basics, but it remains up to the investigator to decide which drugs to try. There are many.  The TCM Database contains 61,000 compounds.  In addition, if you are intending to follow this path seriously then you really should audit your system.  I decided the best way to do this was to find an example of Autodock application of several drugs to several targets and ensure that my results agreed with those published. The best paper I found was the one about  food molecules  which gives several references to the PDB files one would need and covered many drugs from cyanidin-3-rutinoside to curcumin.  My docking of many of those drugs to the selected targets gave the same results to within 10% ( they used Autodock 4 and the new version Autodock Vina is expected to differ slightly - and be better and faster).

Running docking for many targets and drugs can be very time consuming and I fully recommend using Windows Powershell to create scripts to create the necessary configuration files , execute the dockings , organise the output files , analyse the output and place the outcome into Excel for consideration.  you can then set a script running for several targets and many drugs and expect comprehensible output a day or so later.

I should also mention that identification of a drug e.g. curcumin does not mean that it can just be eaten with a predictable effect.  Most of the flavenoids involved are almost insoluble in water and hence the bio-availability is very low unless steps are taken to significantly increase their solubility.

A recent research paper demonstrated for the first time that a stam called GSK3 plays an important part in some myeloma cases.

GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target

In the present study, we demonstrate that MAFB and c-MAF, the most frequently deregulated Maf in MM, are phosphorylated by GSK3, which mediates their degradation.   Pharmacological inhibition of GSK3 targets these phosphorylations and leads to the decrease of MM cell proliferation and colony formation. This study provides the basis for further exploring GSK3 inhibition by lithium chloride (LiCl) in Maf-driven MMs in a clinical setting.
The study provides the basis for exploring what other drugs might inhibit GSK3.

Similarly a recent research paper from Imperial College , London demonstrated for the first time that a stam called GADD45B plays an important part in many myeloma cases by suppressing the natural ability of the cell to die by interfering with the apoptosis signal stam MKK7.

Cancer-Selective Targeting of the NF-kB Survival Pathway with GADD45b/MKK7 Inhibitors

Here, we identify the interaction between the NF-kB-regulated antiapoptotic factor GADD45Band the JNK kinase MKK7 as a therapeutic target in MM.

The study provides the basis for exploring what other drugs might dock with GADD45B in the same place as MKK7 would do and hence the repression of MKK7.

GSK3

I could not find the GSK3 PDB but did find the PDB ID:1Q4L which contains it.  I find Chimera the easiest software to use for manipulation as one can pick sections with a mouse and delete them; to leave GSK3 alone for saving as another PDB file.   This is corrected and minimised as per previous for use in ADT.  My best score as a drug EGCG at -9.6 ( a significant interference).  It is a component of Green Tea. 

gsk3-egcg

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GADD45B

Here we are trying to dock a drug into a position such that another stam will not be able to dock.  Running the docking of 2 stams is just not possible on my PC ( it would take months to run) but luckily there are sites on the internet that will do it for you.  My output from them confirmed that MKK7 docks to GADD45B in the region of LYS395.

gadd-mkk7

So when I do look for a dock, however good it is, it must be in that region.  The best I found ( at -8.4 ) was silibinin, a component of the Milk Thistle.


gadd-sili


Best of luck with your chemistry, it was all new to me!

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