SAR of in vitro, in vivo and LogD values. Questions

[fantasy121]

This work continues on #51

I'm working on the structure-activity relationship of the compounds, based on our discussion in the previous meeting. I'm looking specifically at the LogD values and in vitro and in vivo efficacy of some compounds.

I was able to recreate one of Wendy's plot (below), get the structures of our compounds of interest (data coming shortly, let me work at them a bit more). I've done purple and blue regions, other regions to be completed.

(Red oval and purple oval were the regions of interest that we discussed in our March meeting #47, with purple being the sweet spots (good in-vitro efficacy and low LogD values which is good for in vivo also. I will have a look at some other regions to see if anything interesting comes up. Namely, blue rectangle (LogD too high for in vivo), green ovals (poor in-vitro efficacy, and logD too high for in vivo, double whammy), yellow rectangle log D 2.5[+/-0.5] region (where logD doesn't consistently guarantee high in vitro efficacy, meaning (an)other factor(s) might be at play such as steric (ie: big molecule), black triangle (the outliers). Sorry if you have problems seeing colours, this was only a draft and not presentation-ready yet)

I moved on to some of the vivo data. In the In vivo tab of our Master List, MMV compounds do not contain data of in vitro for % growth at 100 uM. These data are however available in the "MMVBoxes screened" tab of the Master List, but these values are very big and different from the % growth at 100 uM in the "MyOS compounds" tab. For example:

MMV Comounds	% Growth at 100 uM
MMV689244	4165998507
MMV688774 (Posaconazole)	7476718895
MMV022478	8124323453
MMV688754 (Trifloxystrobin)	385375513
MMV688943 (Difenoconazole)	488524737
MMV688942 (Bitertanol)	-373488281
MMV021057 (Azoxystrobin)	1599336647
MMV687807	-2388462274
MMV675968	-466915465
MMV006357	2457997706

Are the above values comparable to the % Growth values found in the MYOS compounds tab? And if yes, can you help me harmonise these values to compare between the databases? @wwjvdsande @Wilson-Lm. It would be nice to be able to add these compounds to the in vitro-LogD scatter plots as well.

For example, EPL-BS1246, MMV689244 is MYOS_00010_00_01 and has the % growth at 100 uM of -4.0 in the MYOS Compounds tab

Also, if I want to recreate these plots below: Where do I find the % survival d10? is this available on the Master List? I can only find "Surival % In vivo efficacy in galleria mellonella larvae (20 uM/larvae)" on there and when I plotted the data, the plot looked a little different from yours. Would "Surival % In vivo efficacy in galleria mellonella larvae (20 uM/larvae)" still be as meaningful as "% survival d10"? My attempt below (did I do something wrong?)

[wwjvdsande]

@fantasy121 I will check the mastertable. The percentage growth of the MMV boxes is wrong. It should be in the same range as those for the MyOS compounds. Probably something went wrong when I used the original Excell file. In the Dutch version of Excell 100,0 is 100% not 100.0.

[wwjvdsande]

@fantasy121 @mattodd @MA-Jjingyi @MFernflower @Wilson-Lm @dmitrij176 I managed to put Excell on the different format and re-entered the data. I also noted that MyOS_00015_00_01 and MYOS_00021_00_01 were swapped somewhere down the line. In the list were we entered the original data (that corresponded at that time still to hpd and dm names) we added the MYOS names just before our last meeting. MyOS_00015_00_01 than correpsonded to hpd3-4 and MYOS_00021_00_01 to hpd30-1. Now it is the opposite around. When I checkted the values in the corresponding rows I noted that not all values were correct, may be that is the difference between your figure and mine. I don't know who did swap the names and when but it will be good for everyone to check the data behind those two molecules. That is always the issue when re-naming. Please all, stick to the list we currently have and if re-naming is necessary for some reason also let the others know.

[wwjvdsande]

@fantasy121 we did compare the azoles with the fenarimols but I'm not sure if we should plot them all in one. The same trends are seen but the values are different for each class

[wwjvdsande]

@fantasy121 I tried to see what was different between your figures and mine but one thing I noted was that you have a logD <2 and many >4. In the master sheet I did not see a logD <2 for the molecules we tested or that many compounds with a logD >4. We had one >5, you had none. Did you use the logDs in the masterlist or did you generate different logD values?