Jim Cronshaw from the Todd group at the University of Sydney here again. It’s been quite some time since I made an update on my research on The Synaptic Leap. This post is intended to give an overview of what problems have been hounding me over the intervening two months.
We're looking to identify a new set of compounds for the next round of optimisation. This is happening in addition to sourcing of commercially available analogues that will fill a bit more of the SAR space but aren't necessarily exactly what we want.
I have been helping out with public searches for the OSM-S compounds. One of the many utilities of PubChem is as a meta-vendor portal. The question immediately arises as to what analogs of the more potent hits might be available for purchase and testing via the outlinks provided in PubChem. I consider myself able and willing to navigate the bioactivity spaghetti links but this is the first time I have done any serious ferreting through the vendor maze. Because this turned out to be unexpectedly difficult I have written a personal blog post that I hope will be informative for the proje
It is common in drug discovery to have a highly potent hit that has to be optimised to remove undesirable characteristics such as poor oral bioavailablity, metabolic stability or toxicity. In our case, we have a number of highly potent compounds that have quite a high LogP, which is considered a warning sign for both a promiscousity (i.e. binding to many compound targets in vitro) as well as poor oral bioavailabilty (as it breaks the Lipinski Rule of 5).
There are over 5 million compounds that are available to purchase according to the meta service, E-molecules (http://www.emolecules.com).
It is worth exploring these in the context of the OSDD project as it will identify compound series' that are very easy to explore by purchasing analogues (i.e SAR by catalogue) aswell as identifying compounds that are potentially more sythetically accessible than others (i.e. if there many close neighbours these compounds might be easier to make than others).
It's exciting as usual on the project. We've submitted the three compounds for in-vivo oral evaluation in a mouse model. The original hits TCMDC-123812 and -123794 were submitted along with one of Zoe's near neighbours, ZYH 3-1. It's not the most active of our compounds with an IC50 of 26 nM, but its logP comes in at just under 5 or there abouts (see: http://www.thesynapticleap.org/node/384#comment-798). It's still pretty high so we'll see how it goes.
One of the interesting features of the GSK set of antimalarial compounds that are acting as the starting point for this project is that they are whole-cell actives, meaning that though they are extremely promising hits, we don't know how they work - i.e. what the targets are. To some extent this doesn't matter - praziquantel has been used for over 30 years and nobody knows how it works.
The idea is to design Potential Kinase inhibitors using Pharmacophore search, Docking, Semantic link association prediction, VROCS and fragment based approach to find novel molecules against Kinases.PASS Prediction
We have received encouraging biological results for the analogues we sent for testing before Christmas. Mat has discussed this here on TSL and on G+. Our best hit came from the "near-neighbour" compound and the original GSK hits came out slightly less active than in their original high throughput screen.
I'm now happy with the data for TCMDC-123812 and TCMDC-123794. A bit of usual practical annoynce with TCMDC-123794 caused some trivial issues, namely a bit of repurification and acetone in the final spectra. These have now been taken care of and the compounds are ready for testing!
