Tuesday, 5 January 2016

Drug discovery

Deniz U, Ozkirimli E, Ulgen KO A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors. J Mol Graph Model. 2015 Nov 12;63:110-124. doi: 10.1016/j.jmgm.2015.11.004. [Epub ahead of print]

Decrease in sphingosine 1-phosphate (S1P) concentration induces migration of pathogenic T cells to the blood stream, disrupts the CNS and it is implicated in multiple sclerosis (MS), a progressive inflammatory disorder of the central nervous system (CNS), and Alzheimer's disease (AD). A promising treatment alternative for MS and AD is inhibition of the activity of the microsomal enzyme sphingosine 1-phosphate lyase (S1PL), which degrades intracellular S1P. This report describes an integrated systematic approach comprising virtual screening, molecular docking, substructure search and molecular dynamics simulation to discover novel S1PL inhibitors. Virtual screening of the ZINC database via ligand-based and structure-based pharmacophore models yielded 10000 hits. After molecular docking, common substructures of the top ranking hits were identified. The ligand binding poses were optimized by induced fit docking. MD simulations were performed on the complex structures to determine the stability of the S1PL-ligand complex and to calculate the binding free energy. Selectivity of the selected molecules was examined by docking them to hERG and cytochrome P450 receptors. As a final outcome, 15 compounds from different chemotypes were proposed as potential S1PL inhibitors. These molecules may guide future medicinal chemistry efforts in the discovery of new compounds against the destructive action of pathogenic T cells.

Many years ago pharma would take their drug library of a few million compounds and screen thousands them against a target with robots...now you can do it with roberts and other people who can sit in front of a computer and make educated guess about what will work before making loads of compounds. 

Whilst, we are not using this blog to talk about our research:-), that is what we did. After a bit of thinking we made about 30 compounds and took one of them all the way into the clinic...

But in this study they looked in the The ZINC Database contains commercially available compounds for structure based virtual screening. It currently has about 90 million compounds that can simply be purchased. It is provided in ready-to-dock, 3D formats with molecules represented in biologically relevant forms. It is available in subsets for general screening as well as target-, chemotype- and vendor-focused subsets. ZINC is free for everyone to use and download at the website zinc.docking.org. This database and service is provided by the Shoichet Laboratory in the Department of Pharmaceutical Chemistry at theUniversity of California San Francisco (UCSF).
In this study that can search for millions of compounds and see if they bind to target but they a
lso looked to see if they hit hERG this is an ion channel found on the heart and is a no no in drug development and another is cytochrome P450 which are enzymes involved in breakdown of these, affect these and you are going to get drug to drug interaction problems and you drug is going to get broken down fast and so another no-no. So they find a number of different chemical types that may block the production of sphinogosine-1-phosphate. Fingolimod down regulates the sphingosine-1-phosphate receptor and so blocking the production may have the same effect of fingolimod. So is this really innovation or should we be looking for new receptors to have new function. 

So going back to our research that we should discuss on the blog according to one punter, we have found a new receptor for a new treatment. You are not going to do this by computer modeling..at least not yet and serepidity can be an alternative 


  1. This looks like a methodology testing, not so much drug discovery per say. Is anybody validating the results experimentally?

    1. Well I do not know if I could call "innovation" because you are not creating anything, just giving a new purpose to something that already exists. But is faster and viable alternative, compounds already exist, are already filed and available just need to see if the proposal is to focus. It was what they did with the Clemastine and the MCC950 for example ...


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