Signal Transduction

We read a lot about inhibitors, activators, agonists, antagonists which modulate (adjust/alter) enzyme or cell-receptor function and thus reducing/preventing the illness. 

For example, kinase inhibitors as cancer theraeupatics;  PPAR agonists as antidiabetic agents.

But the story doesn’t end when an inhibitor or agonist binds to an enzyme or cell-receptor, respectively.  These inhibitors or agonists do not directly (in a single step) affect the illness.  There are several intermediary steps (cascade of events) after the initial binding which bring about the finally observed biological response.  Agonist/Inhibitor binds to cell receptor (first step, called reception) which will send signals within the cells, and this signal is passed (transduction) to the necessary location via several helping hands (say enzymes).  At last the response is observed.  Let me show a pictorial representation of this explanation.

Synthetic organic chemists can correlate the cascade of events which I mentioned earlier to cascade reactions in organic synthesis. 

Let us imagine ‘+’ charge as signal.  Now this signal has to reach from carbon circled in red to the carbon circled in blue of compound 1.  Compound 1 can be imagined as a cell receptor in inactive state.  Once TFA is added (imagine it to be an agonist), ‘+’ signal is generated.  Now this ‘+’ signal has to reach the final destination i.e. to the carbon circled in blue of compound 1.  By the help of several unsaturated functionalities both double and triple bonds (helping enzymes which facilitate transfer of signal) circled in blue in compound 2, ‘+’ signal reaches its destination.  Formation of compound 4 via compound 3 can be viewed as the final response of the signal.



Medicinal Chemistry Newbies: Leave behind all your preconceived notions [Example 1]

Presumably, most of you might have encountered people saying “not to have a Michael-acceptor moiety” in your molecules.  This is due to the fact that nucleophilic species present in proteins (mostly cysteine residue) would bind to the Michael-acceptor moiety of drug thus making it unavailable for the required purpose.

 

Now the question is, Should we always be terrified of incorporating such Michael-acceptor moieties in our molecules? Answer is both Yes and No  

Recently, there was an article in J.Med.Chem. 2010, 53(7), 2719-2740 describing several moieties (substructures) featuring in molecules which are frequent hit compounds in many biochemical high throughput screens.  In this article there are a number of Michael-acceptor substructures which were described as ‘pan assay interference compounds’ (PAINS).  Any protein reactive compound comes under PAINS.  Authors go to an extent saying that such compounds are polluting scientific literature and causing nuisance.

   

On the other hand, in a review article published in Curr.Med.Chem2009;16(13):1596-629, rhodanines were called as ‘privileged scaffolds’.  Success stories of Epalrestat an aldose reductase inhibitor and glitazones (type II diabetes) were shown as examples.

 

Moving forward, efforts from Prof. Klein’s research group (Heidelberg University) provide some more insights into the biological activities for rhodanine and realated five-membered analogues.

http://pubs.acs.org/doi/abs/10.1021/jm201243p

From their own results and the literature precedents, they conclude that the so called ‘promiscuous or frequent hitters’ property of rhodanines and thiohydantoins with a exocyclic sulfur atom is not related to ‘unspecific’ properties such as aggregation or reactivity, but rather to electronic and hydrogen-bonding properties.

Justification: There are significant differences in the H-bond acceptor properties of C=S and C=O, with the sulfur having a more diffuse lone pair electron density distribution around the sulfur and frequently interacting with three and four hydrogen-bond-donor groups.  [energetics of H-bond to sulfur in C=S is inferior to those of oxygen in C=O].  However, in the context of protein-ligand-interactions, the desolvation of the ligand has to be considered (breaking of hydrogen bonds to water prior to protein binding), and the free energy penalty of breaking a ‘strong’ C=O hydrogen bond to water may result in the overall ligand binding process being more favorable for the C=S group.  In water, the stricter geometric requirements of the C=O group as hydrogen bond acceptor can more easily be satisfied than in protein-ligand complexes.  When a ligand has to ‘adjust’ to a geometry that is predefined by proteinaceous receptor, the more geometrically tolerant C=S group, which is also able to form a larger number of hydrogen-bonds has more flexibility to adjust its intermolecular interactions to the given requirements.  Thus, this property of C=S makes rhodanine scaffolds prone to bind to a large number of biological targets.  FINE TUNING might give EXTREMELY GOOD COMPOUNDS?

Now the conclusion to all of you is ‘to be open-minded’.  As newbies, one has to learn the concepts but do not have ‘preconceived notions’ that all the concepts should be taken for granted.  As you gain experience, you will be in a position to distinguish things clearly.  But for now, be open-minded and do not trash any result or publication just based on ‘mis-conceptions’ you heard of.   Concepts are correct but may not be applicable for every therapeutic area or biological target.      
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Hello Newbies [with Organic Synthesis background] to Medicinal Chemistry field: Steps for newbies to medicinal chemistry

Many questions like 'Where to start?', 'How to start?' arise as a newbie to any field.  Medicinal chemistry is no different.  To be frank I am still educating  myself to understand this field.  I am not going to teach or provide any lecture notes here.  However, by following these posts you might end-up understanding how to approach medicinal chemistry projects, different steps involved in the project i.e. starting from initiation towards progress of the project to next levels.

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The most important barrier for the newbies to the medicinal chemistry field is ‘confusion’.  The kind of questions lingering in the minds might be one of these 

– should I first read biology text books 

– should I first read the underlying cause for the disease we are working on 

– should I first read the basics of the therapeutic area we are currently working on 

– should I first concentrate on the relevant biological target of interest 

– should I first read ----- goes on and on.

Let us get out of this confusion.  Try to pursue the following method which will make you feel comfortable, relaxed and confident towards escalating your interest towards this field.

Step 1: Learn to read the biological data [terminology usage] – This is the first and foremost step which everyone has to understand at the earliest.

Step 2: Literature on the biological target you are working on

Step 3: therapeutic area basics, biology related portions.

Step 2 and 3 can be performed simultaneously with Step 1

Medicinal Chemistry

I will be posting few basic medicinal chemistry concepts of every medicinal chemist's interest very soon.  Literature citations likely will help you to get the detailed concepts.

I wish and hope this blog will act as One-Stop Centre  for all the new entrants (specifically, for researchers with chemistry background) to the field to gain basic understanding of medicinal chemistry research.