Change properties of approved oral drugs

When I learned drug discovery long time ago, I read the article about Role of five which is a rule of thumb to evaluate druglikeness.
You can read nice review about the druglikess scores in following URL.
( Written in Japanese ;-) )
View story at

By the way, recently there are many articles which are describing about beyond the Role of five . I read an article published from JMC, reported by researcher of NIB.

The author analyzed the change over time of properties such as MW, logP, HBA, HBD, TPSA and NumAromaticRing.
In page B, the author reported comparison between experimental and calculated (StarDrop, Pomona, Moka, Crippen) value of LogP which is determined in Novartis. And the experiments shows that StarDrop gave the lowest variability between measured and calculated logP. Most of tools overestimate in high log P area but stardrop does not. It worth to know that clogp is largely affected by computational tools.

In Table5 shows analysis of FDA approved oral NCEs from 1998 to 2017. Mw, RotBm and #ArRNG showed significance.
For example 90th percentile of Mw is 571.0 compared to 1997 90th percentile 470.3. It dramatically increased!
And also 90th percentile of #ArRNG is 4 compared to 1997 90th percentile 3.
Mw is changed dramatically I think. Fig 6 shows Number of ratio of MW in approved drug in each time period. This figure shows tendency to decrease of ratio of the drug which has MW <= 500.
By the way, HBD is not changed.

The author discussed about why size (MW) is matter and described that higher molecular weight is not be indicator of druglikeness but be estimator of synthetic accessibility.
To synthesize molecule with high molecular weight, it needs more building blocks and / or longer synthetic steps. So it is needed more effort to SAR expansion in medicinal chemistry projects.

Ro5 is easy to understand and reasonable role for medicinal chemistry but it is changing. Recently there are many modalities for drug discovery.
Changing role is needed long time and many efforts…..
More details are described in the article. It is informative for me.


Applicable Domain on Deep Neural Networks #JCIM #chemoinformatics

I read interesting article from JCIM.
Dissecting Machine-Learning Prediction of Molecular Activity: Is an
Applicability Domain Needed for Quantitative Structure−Activity
Relationship Models Based on Deep Neural Networks?

URL is below.

The pros of DNN is feature extraction. And there are many articles which use DNN for molecular activity prediction. BTW, is it true that DNN is outperform any other machine learning methods?

The authors of the article analyzed the performance of DNN. They used ECFP4 as an input feature and predicted biological activities extracted from CHEMBL DB.
Their approach was reasonable, they built model with training set and check the performance with test data and evaluate RMSE in several layers which are defined by molecular similarity. Layer1 means that dataset is similar to training data and Layer6 means that dataset is not similar to training set.

They analyzed performance of predictive method such as KNN, RF and DNN and their analysis revealed that DNN showed similar performance with RF and KNN. And also Fig 5 shows that DNN can not predict objective value when query molecule is not similar to training set.
It indicates that DNN does not learn feature of molecule from finger print but learned pattern of fingerprint.
More details are described in this article.
In the real drug discovery project, MedChem sometime designs not seed similar compounds. For the chemist, this is not so special. But it is difficult point for AI to learn sense of MedChem.

Biological activity prediction is challenging area I think, And ECFP is still de fact standard for chemoinformatics. I would like to develop new concept of molecular descriptors.

(new?) medchem tool box for compound synthesis

This mini perspective shows recent progress of the direct C-H alkylation with Alkyl Sulfinates.

There are many heterocyclic moieties such as pyridine, pyrrole etc. in drug like molecules.
The C-H alkylation reaction of heterocycles is useful but difficult to conduct it under mild reaction conditions.
So mild and universal reaction is very attractive for chemists I think.

In the article, Phil S. Baran’s group reported many examples of their developed reaction.
They used alkyl sulfinates as a radical precursors and developed many kind of commercial sulfinates, fluoroalkyl, heterocyclic, alkyl, aromatic and linker-type.

Surprisingly most of the reactions proceed room temperature. Also they shows reactivity guid lines, it is very practical!

And also this reaction can apply not only early stage of synthesis but also late stage of synthesis.
It means that this is very specific reaction.
I had few successful cases C-H alkylation with sulfinate…. I would like to use the reaction condition when I have chance.


I like my town. This town is comfortable for me to live in, because it is not too urban like Tokyo or rural.

There are many beautiful place and following pictures are my favorite place.  The water in this river is very clean. I can see firefly in summer around here.

I want to  this scenery to continue forever.

After walk, I went to see a doctor, my finger is getting well. I hope my finger get well soon…

Enjoyed RDKitUGM2018 #RDKit

I got back Japan from Cambridge today. Time flies when you’re having fun.
This is the first time I participate RDKit UGM and RDKit Hackathon. It was amazing experience for me.
Twitter Hash Tag was very attractive. If reader who is interested in, I recommend to search #RDKitUGM2018 in twitter.
I could talk face to face many people who I’m following twitter. Thank you for talking with me. ;-)
There were many exiting topics in the meeting. Especially I enjoyed Dr. Segler’s talk about computer aided synthesis planning. It was nice work! His system can analyze retrosynthetic route very efficiently.

And Gregs’s presentation gave me very important message.
Pros of open source is good community and contribution of users. I agree his opinion. I would like to have ab internal discussion about it.

I really surprised that I could meet my blog reader and could get many positive comment about the blog.
I was so happy that I cried….

This blog is memo for myself, but it make me happy that my blog be someone’s help.

I really thank the meeting organizer and participants.
I hope I can meet everyone next year

Enjoy summer vacation

I and my family enjoyed camp in this weekend. This is third time for us.
The campsite is located near the river. Kids enjoyed playing in the water and caught crabs.

This tent site was very humid because after a typhoon has passed. It was
terrible dew condenses on the tent….

In this morning, I enjoyed coffee and hot sand. My new partner, coleman 413H 2 burner worked very well. It made us delicious breakfast. ;-)

I would like to go camp again near the feature!