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Sunday, August 12, 2012

Kinase compounds polypharmacology can it be studied using Mol Wt & Lipophilicity


I have came across a post in blog FBDD and also from the linkedIn groups about the effect of liphophilicity and Molecular weight in promiscuity. Peter have referred one very good paper from Michael Hahn and Andrew Leach of Molecular complexity and fragment-based drug discovery: ten years on .This review suggest the importance of liphophilicity, Molecular weight,positive charge , Heavy atoms count in promiscuity.According to the paper Molecular complexity is playing a crucial role in polypharmacology. 
My Question is here what do you mean by molecular complexity? 

From the paper they have mentioned the use of mol weight and heavy atom count to in molecular complexity.Several studies were made for example 75000 compounds from pfizer were tested against 220 assays ,they showed that promiscuity decrease with mol weight, to counter it Novartis did 160 HT assays were they found a postive effect of mol wt in promiscuity.They also found that compounds containing a carboxylic acid showed significant higher selectivity.Other than that sprinthorpe seminal work proposed that increased liphophilicity and presence of basic moiety is playing a important role in promiscuity. From the paper mentioned"People at Roche also mentioned presence of positively charged groups and increase promiscuity."

Based on leach paper i did some study of 72 known Kinase inhibitors which was assayed against 442 different kinases studied by Davis etal . The 72 different inhibitors are available at https://www.ebi.ac.uk/chembldb/target/inspect/CHEMBL1908385 .


I used AlogP for liphophilicty, mol weight, polar surface area and Heavy atoms count against the selectivity score of the compound ar 3 uM. The kinase selectivity score at 3uM is defined as the number of kinases the compound is bound at 3uM to the total number of kinase domain queried.The selectivity scores are being distributed between 0.2 nad 0.7  the The data is available in as additional file in  http://www.nature.com/nbt/journal/v29/n11/full/nbt.1990.html . They have observed "The lowest selectivity scores, and therefore the greatest selectivity, were observed for the MEK inhibitors AZD-6244/ARRY-886 and CI-1040, the MET inhibitor SGX-523, the CSF1R inhibitor GW-2580 and the ERBB2/EGFR inhibitor lapatinib (Tykerb)."

The figure below explains an interesting result. For liphophilicity there exist a negative correlation but for all other it was positve though the correlation was maximum for mol weight around 0.31 but PSA and heavy atoms count it was below 0.1. Both the figure displaying same type of distribution of compounds at 300nM and 3 uM in which lower selectivity observed for different classes of kinase inhibitors.

 


Most of the compounds studied was having a selectivity below 0.2 which indicates the selectivity of class I and class II. For class I and class II inhibitors they are not much a difference Class I was made for big gate keepers like phenyl alanine and class II made for small and medium gatekeepers.Figure below gives the distribution from selectivity scores of different classes of inhibitors from Davis paper.

I think more compounds needs to get explored for the study of kinase inhibitor selectivity and prosmiscuity. Does these signify that the kinases are selective for compounds? 
However i still have question what other property comes into molecular complexity when dealing with promiscuity?
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