## Friday, February 14, 2014

### Converting Similarity Matrix into a into a pairwise p-value

We can calculate the probability that a given random pairwise similarity score X is bigger than a value x as p(X > x) using the fitted Gaussian function, we can transform a Tanimoto similarity matrix into a p-value p(X > x) as follows:

were t(xi,xj) is the tanimoto similarity matrix and h is the smoothing factor which you need to estimate.

Hope now you all can very easily understand how you can calculate your pvalue from a large distribution.

## Tuesday, October 22, 2013

### Fast Tanimoto Similarity Calculation using rcdk

Well many of you ,who are using r for cheminformatics must be knowing rcdk . Regarding the tanimoto calculation i have seen it seem it takes a long time to calculate the code in rcdk code looks neat but still the similarity calculation can be performed much faster using the inner products.Below given a simple code to do that and also the time taken is like 10 times faster than the rcdk code. Quite an impressive performance boost . I have made a pull request to Rajarshi's code, it should be available soon in the main package.

##Consider m is the binary matrix of 0 and 1 which you calculated using fp.sim.matrix###

Time taken for the new method
user  system elapsed
2.962   0.012   2.971

#Normal method in rcdk

user  system elapsed
43.644   0.064  43.707

### Dynamic plots with R Studio.

Few days back i came to know that R Studio provides dynamic plots like you can plot histograms and move sliders, tick check boxes and also you can select from the drop down list the items you want to display from your dataset.I will provide some examples of this below. Quite cool enough from Rstudio group.

//Sliders
library(mosaic)
if(require(manipulate)) {
manipulate(
histogram( ~ eruptions, data=faithful, n=n),
n = slider(5,40)
)

}

//CheckBoxes
library(mosaic)
if(require(manipulate)) {
manipulate(
histogram( ~ age, data=HELP, n=n, density=density),
n = slider(5,40),
density = checkbox()
)
}

Check box with density plot

//Dropdowns

library(mosaic)
if(require(manipulate)) {
manipulate(
histogram( ~ age, data=HELP, n=n, fit=distribution, dlwd=4),
n = slider(5,40),
distribution =
picker('normal', 'gamma', 'exponential', 'lognormal',
label="distribution")
)
}

//dropdown and density

library(mosaic)
manipulate(
histogram(as.matrix(mtcars[,factor]),
beside = TRUE, main = factor,density=density),
factor = picker("mpg", "disp", "hp","drat","wt"),density = checkbox())

This way you can make your ggplots dynamic with the manipulate package.

## Monday, July 22, 2013

In January, I started  doing an interesting project using random walks to predict drug -target. I found many papers got recently published in this domain one is by Chen and another one from Xing Chen . Looks interesting work and there are several papers related to this topic you can just type it in google .

Now the point I am trying to indicate is that the molecular descriptors which they used is kind of ok or not. I made  descriptors based study too in which some pharmacophore descriptors gave me very good results.
The validation is still an important question. Ok, if you have got some model you need to test
your data. Looks like in these papers they didn't show  cross target class validation much which made me to do research on the method. Well i am still onto it.But today i will be posting some of the interesting results i got while working with the random walk with restart algorithm or you may call personalized page rank /shortest paths etc.

A random walk is a ﬁnite Markov chain that is time-reversible  In fact, there is not much diﬀerence between the theory of random walks on graphs and the theory of ﬁnite Markov chains; every Markov chain can be viewed as random walk on a directed graph, if we allow weighted edges. Similarly, time-reversible Markov chains can be viewed as random walks on undirected graphs, and symmetric Markov chains, as random walks on regular symmetric graphs.

A random walk on Graph starts at a node x and iteratively moves to a neighbor of x chosen uniformly at random from the set (x). The hitting time H(x,y) from x to y is the expected number of steps required for a random walk starting at x to reach y. Because the hitting time is not in general symmetric, it is also natural to consider the commute time C(x,y) := H(x,y) + H(y,x). Both of these measures serve as natural proximity measures and hence (negated) can be used as score(x, y).

Now,  some results

Figure  shows the statins network and the top scoring 10 predicted genes are listed for the compounds along with the true links. The true links are coloured in blue solid lines and red dashed lines are the predicted network.It has reported that both lovastatin and simvastatin having the side effect of alopecia and hair loss along with post marketing side effects shows variety of skin problem related to these drugs such as nodules, discoloration, dryness of skin/mucous membranes.

We have found an association of simvastatin and lovastatin with KRA53 and KRA52 genes. KRA53(Keratin associated protein 5 type 3) is an essential gene for the formation of a rigid and resistant hair shaft through their extensive disulfide bond cross-linking with abundant cysteine residues of hair keratins. The matrix proteins include the high-sulfur and high-glycine-tyrosine keratins.  The majority of keratinizing disorders affect the epidermis and/or its adnexal structures such as hair and nail, or sweat and sebaceous glands, although a number of these diseases affect other epithelia such as mucosal or corneal epithelia. We hypothesize here the side effect of hairloss of lovastatin and simvastatin might be associated with KRA53 or KRA52.

The method also shows some very good results listed in the table below. Overall combination of sequence and descriptor similarity performs good. But still is it good enough to predict cross target class prediction. Well we have to see and validate more .

 Drugs Targets zolmitriptan Dopamine D1 Receptor, Dopamine D2 Receptor Lamotigrine Sodiumchannel protein type III alpha subunit, sildenafil adenosine A2A receptor, adenosine A2B receptor Timolol adrenoceptor alpha 1B Acetaminophen PhospholipaseA2,PPARG, phosphoglycerate kinase 1 Glipizide Alkaline Phosphatase,PPARD,Multi drug resistance protein Pyridostigmine Liver carboxylesterase 1, Acetylcholine receptor subunit alpha fluocinonide Synaptosomal-associated protein 25, Metronidiazole Beta-2 adrenergic receptor Doxazosin 5HT2A

## Thursday, December 13, 2012

### Drug Repurposing Explorer

Following from the previous work i have made an tool suitable for drug repurposing using the side effect, Protein sharing, Fingerprints(Pubchem, ECFP6) and also ROCS (3D) .

I collected tThe side effect information of 727 drugs from SIDER .The target information, ATC Codes
from the Drugbank. We also manually added some of the drugs ATC codes from KEGG database. The
disease information of 727 drugs was obtained from Comparative Toxicogenomics Database (CTD)
[8].CTD is a curated information resource for chemical- gene, chemical-diseases, gene-diseases, chemical
–ontology interaction which is curated by hand by the CTD bio-curators. We extracted the Chemical to
disease association between the compounds which are related to the therapeutic area only which will help
to identify possible diseases to treat the drug and also if new diseases could be identified. We then
converted side effect and target data into binary matrices of 0 and 1 and created drug-side effect, drug
target matrices.

A user searching for a drug in Drug Repurposing explorer should be aware of drug  and also for what purpose it is used.

If any user using this tool found something interesting please mail your results to abseal@indiana.edu or djwild@indiana.edu. It will help to make a good manual for the user while searching the database.

## Sunday, November 25, 2012

### fingerprints,fragments,side effect of drugs...

After a long time i am writing a blog . Though the material looks quite interesting to me for study the results indicate some essential fingerprints are related to side effect profile as well the compounds therapeutic area and also in target similarity between two compounds.

So lets see what the study tells....

I mapped around 746 compounds from drugbank and SIDER  by CID and then by name of the compounds and  manually checked and made a final dataset for my study. The recent SIDER provides 4500 side effects profiles.The side effect profiles are used to create a Compound - side effect binary matrix .

The side effects are used to calculate the compound similarity using matrix multiplication and normalization the algorithm i used is discussed in paper Metapath . It provides a fast and efficient way to calculate dice coefficient which i used to calculate the similarity more at Rajarshi's Guha Blog .

For the Final data of 746  compounds i removed metals and compounds molecular weight greater than 1000  and ultimately came down to 728 compounds.

I also created a compound- target matrix and compound - atc code matrix ( data is collected from drugbank) from which I calculated the similarity of compounds by side effect, ATC codes and protein  using using the metapath algorithm respectively.

Earlier research from Yamanishi's work on predicting side effects from substructure profile and drug target prediction using learning models  were very good papers . One of the important paper was from Campillos of drug target identification using side effect similarity which focused on similar side effect profile which is kind of similar to the off target profile. Another paper (SLAP) from our lab at Indiana University using semantics to identify target was a good improvement of integrating multiple heterogeneous network and predicting targets.

For my work i used pubchem fingerprints, maccs keys 166 , ECFP 4, ECFP 6 FCFP 4, FCFP 6 to find how much is the relation between the these fingerprints with the side effects and ATC codes and proteins.

I used Tanimoto similarity for the fingerprint based similarity of compounds and the pathsim similarity with side effect,ATC and protein of compounds. After performing a simple correlation study I found pubchem fingerprints are highly correlated with side effect though the correlation is about 0.16 but it was statically significant p-value < 2.2e-16 so as for  maccs keys and extended connectivity fingerprints. Below i provide correlation matrix of the different fingerprints,side effects,ATC Code, protein similarity.

 Pubchem Fingerprint similarity Distribution

 side effect distribution
Below is the matrix shown

 sideffect pubchem maccs ECFP4 ECFP6 FCFP4 FCFP6 atc protein sideffect 1 0.160535 0.156551 0.142548 0.140111 0.125838 0.12807 0.055374 0.097784 pubchem 0.160535 1 0.585017 0.604037 0.566609 0.617526 0.576539 0.018368 0.132186 maccs 0.156551 0.585017 1 0.523484 0.491311 0.477387 0.434868 0.014732 0.169165 ECFP4 0.142548 0.604037 0.523484 1 0.990811 0.757584 0.777071 0.096187 0.289458 ECFP6 0.140111 0.566609 0.491311 0.990811 1 0.747782 0.787673 0.102716 0.295364 FCFP4 0.125838 0.617526 0.477387 0.757584 0.747782 1 0.981399 0.094613 0.263978 FCFP6 0.12807 0.576539 0.434868 0.777071 0.787673 0.981399 1 0.106107 0.283874 atc 0.055374 0.018368 0.014732 0.096187 0.102716 0.094613 0.106107 1 0.166476 prot 0.097784 0.132186 0.169165 0.289458 0.295364 0.263978 0.283874 0.166476 1

It is found that ECFP and FCFP  shows very good correlation with Protein and atc code similairty fingerprint . But on the other hand pubchem fingeprint shows a best correlation with the side effect .
A question is arised here if the correlation is such low how much does Yamanishi's paper is able to predict the true relations? Can different substrctures methods able to correlate with the side effects ?

Well i am still thinking what's behind the side effects and the impact of right substructures on side effects.

## 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?

## Saturday, August 11, 2012

### PCA Plot

Continuing from the last post i have done some PCA anaylsis using 12 different physicochemical property descriptors including molecular refractivity, atom polarizabilities, bond polarizabilities, hydrogen bond donors and acceptors, petitjean number, topological polar surface area, number of rotatable bonds,liphophilicity XLogP, molecular weight, topological shape and geometrical shape.

I used CDK for this developed by Rajarshi Guha and plotted the plot using ggplot2

Quite impressive that the compounds which have been screened was in the same area of the PknB inhibitors. Some outliers like Mitoxantrone,straurosporine are their which are scattered in plot . But majority of the predicted ones are in close association with the PknB inhibitors.

## Monday, August 6, 2012

### Pharmacophore study for Mycobacterium tuberculosis Ser/thr kinase (PknB)

Pknb Study

This posting is to give you the idea about recent research i have done in Mtb PknB. Previously i have reported some of the predicted inhibitors. Now this time i am again updating some of the research done in identifying more inhibitors.I am here in India from June 21 to august 20 th 2012 under IUSSTF  science and technology scholarship at Birla Institute of technology hyderabad campus.

Previously some work had been done here on PknB inhibitors.(paper under publication),with collaboration with OSDD.They have identified some inhibitors under 1micro molar concentration . Well quite impressive!!
But the problem with the PknB is that the inhibitors are not capable enough to inhibit the growth in cell line study.

Why is this so?

Is it due to the mycolic acids barrier which don't let compounds to enter the membrane.Not sure about this But more research needs to be done on the branch of drug permeation.

I set my target as PknB which i had been doing earlier and a recent paper by Lougheed team helped me to study the compounds well and also it's pharmacophores.Previously they also reported another group of inhibitors in a paper which was not so much potent as the current ones.But the study done by me helped me to identify the main pharmacophore behind these structures.

PknB a kinase so what it could be a typical kinase like pharmacophore. having hydrogen bond donor's and acceptors and hyrophobic moeity for example class I type inhibitors. Thanks to Jae hong shin  for good presentation on kinase inhibitors which helped me to study the inhibitors of PknB.
 Kinase Inhibitors and its pharmacophoric positions.

From a review paper by Zhang etal Targeting cancer with small molecule kinase inhibitors  given in  the pic above we can see most of inhibitors and its scaffolds the basic pharmacophore looks like which is given below having 2 donors and one acceptors and big hydrophobic moiety.

 Different types of Kinase pharmacophores.
 List of published PknB Inhibitors.

The features of the kinase pharmacophore completely resemble inhibitors identified the Lougheed team. I collected  62 Inhibitors with IC 50 values and generated E-pharmacophore based on the compound VIII given in Figure below.E -Pharmacophores are based on the Energetic contribution of the group of atoms to the receptors .It is generated from the Glide XP descriptors. After docking the 62 compounds compound I showed the best docking score followed by compound VIII and then it was Mitoxantrone. I generated pharmacophores for three compounds.
The pharmacophore  for compounds was resembling the typical kinase class-I type pharmacophore. I did some enrichment studies and BEDROC scores and AUC studies and found the pharmacophore for compound VIII was most appropiate for PknB till now from the dataset I collected. If anyone wants the dataset of 62 compounds email me at abseal@indiana.edu.For enrichment study 1000 decoys were collected from Schrodinger's website. The pharmacophore was having a high enrichment at 1% ,2%  and 5% of the database hits.
The paper by Salam etal on E-pharmacophore mention the choice of sites which have scores greater than -1 kcal/mol but i have a different scenario here . The ring aromatics score was less than -1 Kcal.mol and one extra donor was  having less than -1kcal/mol score. Still my selected pharmacohore was giving a very good enrichment results.
Not sure anywhere does selection of sites based on the energetic contirbution or not.But i selected the sites based on the structure of a typical kinase pharmacophore. The picture given below represents my pharmacophore .The previous work done not published didn't considered the extra donor D6 on the bottom right side. This donor has some special effect for most of the compounds when this donor site is present it brings down the IC 50 value below 0.1 micro molar which indicates that this is one of the important sites.

The docking pose of the compound is also given below for compound VIII along with the pharmacophore

I have done data fusion using the structure and ligand based methods  pharmacophore ,glide and rocs and  using sum score, sum rank and reciprocal rank . Well reciprocal rank is amazingly performing well giving me one of the best enrichment scores along with a BEDROC value of 0.875 and RIE 12.73.Also the AUC for 1% ,2% and 5% was 0.71,0.75 and 0.81. The next datafusion algorithm worked very well was sum score method with BEDROC of 0.785. Both the data fusion methods performance was better than usual Virtual screening methods.

I have done some screening using the datafusion methods using the Asinex screening library. Will post some materials in next post.