Thin book of chemoinformatics_en #chemoinformatcs

I really happy to having the opportunity for writing the thin book of chemoinformatics. I want to express my gratitude to @fmkz__.

The book is written in Japanese and I got some request from my follower about English translation. It is tough work for me, I thought it will take long time to do it. However, fortunately wonderful co-workers appeared! And the work goes well. Thank joofio and I am happy to work with him.

Today I just finished making English version PDF. Then I sent PR to the repo.

Draft version can get from my github repo.

I will be happy if it is useful for someone who is interested in chemoinformatics. The book has some sample jupyter notebook code. So readers can run the code on your PC.

By the way, I would like to introduce the girl who is in cover picture.

Her name is ‘Kusuri Murakumo’ called ‘Souyaku-chan’. She is a child of social drug discovery. ;)

Souyaku means drug discovery in Japanese. She organized drug discovery competition. It is very exciting event for us. Recently there are many open source tools for drug discovery. So if you want, you can do virtual screening on your private PC. Some years ago foldit solved complex protein structure with gamification technique. She tries same manner to discover new drug. It seems interesting isn’t it?


2019度初試合 #dodgeball







HTS with micro-fluidic instrument and DNA encoded library. #DEL #HTS #memo

DNA Encoded Library (DEL) is one of powerful tool for HTS. Recently there are many CROs however the approach has limitations. It is limited to affinity-based hit identification. It is difficult to apply insoluble, instable targets. Today I read an interesting article reported by researchers from Roche and Scripps Research Institute. The URL is below.

Activity-Based DNA-Encoded Library Screening

The authors made DEL as ‘One-bead-one-comound’ library and the compounds and beads are linked with photo cleavable linker.

Figure1 in the article shows whole structure of their assay platform. They selected Autotaxin as a screening target. I had an interest in the assay platform. The assay of each compound is performed in a droplet. Laser-induced fluorescence assay detection was used and then hit droplets are separated by difference of voltage AC pulse.

You can see movie of the instrument in supporting information.

They prepared 67100 membered DEL and perform the miniaturized HTS campaign. The throughput of the assay was 30000 beads per hour! And got ~7000 hits with good Z'(0.71).

As a result of the screening the authors get some novel chemical series as hits.

Amazingly, it was required only 8h instrument time and consumed vanishing quantities of activity assay reagents (<10 μg ATX; < 20 nmol substrate) and library (0.0005 total library). Even if huge amount of compounds are assayed.

I think it is difficult to understand the technology from my post. I recommend to read the article.

Integration of cutting edge of science and technology produces new solution for drug discovery. I hope the technology accelerates drug discovery project for human health.

Enjoyed SPARQLTHON and weekend #memo

In this week I participated SPARQLTHON #78 where held on national institute of genetics.

I am not familiar to SPARQL so it was difficult to develop something with SPARQL, but I tried to use SPARQLWRAPPER which is package for using sparql from python and tried to retrieve information from ChEMBL RDF.

It was good opportunity for me because I could focus on coding and after the hackathon, I could have many fruitful discussion with other participants. I was surprised that traditional analytic method is more useful than deep learning in the area of genetics. Because physicochemical properties control genetics so found rules such as Mendere law are stronger than traditional machine learning methods. Deep learning is useful but I have to consider the case when it will be effective.

And this weekend I and my kids went to cherry-blossom viewing party. In Japan, current season is good for the event. There are many cherry-blossom. It is really beautiful and temperature becomes warmer. I like the season expect be suffering from a hay fever.

Here are some photos of cherry-blossom. Tomorrow is the beginning of a fiscal year. I will enjoy and do my best.

Efficient site-selective functionalization with TFT #organic_synthesis #organic_chemistry #memo

There are many new functionalization reactions of molecules in these days such as electrochemistry, photo-redox and cross-coupling etc. New reaction will give more choices for synthetic route.

Chemists often use cross coupling or another functinalyzation reactions, but these reactions are required foothold such asAr- halogen or ArOTf groups. And the reaction precursor is synthesized by using halogenation when the compound is not commercially available.
So, I think direct C-H activation reaction is an attractive but I had very few experiences in my project because it often has selectivity and/or functional group tolerance issue. But!!!! today I found an exciting article from Florian Berger’s group in nature.

URL is below

The group developed new C-H functinalization chemistry with thianthrene derivatives(TFT). In their reaction, cation radical is generated with TFT and TFT sulfide at first and the the radical reacts the substrate and produces thianthrenated intermediate. The reaction can be conducted with high site selectivity and good yield. And also the reaction is not affected with small amount of water, and oxygen. It means the reaction handling is very easy I think.

In the Fig2 shows many example of the thianthrenation. Most of the reaction proceeded moderate ~ high yield and good selectivity with very wide functional group tolerance. The reactivity is controlled with electronic condition of the substrate if target aromatic ring has electronwithdrawing group they used non fluorinated thiantherene instead of TFT.

And following section the authors shows the wide range application of the intermediate.

The thianothreated intermediate can be used for many reactions, transition metal catalyzed cross couplings such as carbonylation, suzuki, sonogashira, negishi, heck and sulfonynlation and photo redox catalyzed reaction such as borylation, phosphonylation, cyanation, pseudohalogenation(ex. SF5), chlorination, idonation.

There are many applications!

In fig3 the author showed many example of these reactions. One is Strychinine acylation. The yield was 48% in 2 steps. Strychinine is an alkaloid with complex molecular structure, normally it is difficult to conduct direct C-H functionalyzation but can do it by using the reaction.

I would like to use the reaction if I have chance. ;)

卒団式に行った話 #diary #dodgeball







Recent trends of Flow Chemistry #memo #chemistry #technology

I enjoyed reading the article in my lunch break. Researchers at Abbie published nice review about the flow chemistry in the pharmaceutical industry. The URL is below.

The review describes wide range of the flow chemistry from large scale synthesis to lab scale synthesis.

Flow chemistry can run the reaction under high temperature and high pressure reaction conditions. Photo redox reaction is also available. I like rearrangement reactions because the reaction is atom economic and stereo selective I feel it is elegant. But theres reactions often requires high temperature condition. In scheme 10 shows example of Overman Rearrangement with flow. The example shows >95Kg scale synthesis in 84hr! Continuous synthesis is powerful tool for production.

One of the strong point of flow reaction is flush chemistry that can conduct reaction in very short time. It means the method can handle unstable(reactive) intermediates. In scheme 15 shows flow synthesis example of Eribulin intermediate. You know Eribulin is a laboratory-made form of halichondrin B, a substance. It has very complex structure. The researchers conducted DIBAL-H reduction of ester to aldehyde and then conducted julia coupling type anion addition. To use flow reaction reaction temperature was raise up from -70 deg to 10 deg.

There many examples are described in the article and scheme35 Flow diazomethane chemistry seems very useful. Diazomethane is useful reagent but sometime it is difficult to use in lab for safety reason so TMS-diazomethane was used. But TMS-diazomethane is not cost effective. The Scheme35 shows example tube-in-tube reactor. What is tube-in-tube reactor? I would like to draw the image below. The inner tube is made with teflon AF-2400 which is gas-permeable tube. The tube can through diazomethane only so outer layer trap CH2N2 and generate pure CH2N2/THF solution. I have not known the technology. It is cool. Reader who has interest, pls read the article.

___________________________________________________ outer tube
THF>>>>>>>> CH2N2/THF
___________________________________________________ AF2400
Diazald+KOH >>> CH2N2 aq + side products >> side products
___________________________________________________ AF-2400
TFH>>>>>>> CH2N2/THF
___________________________________________________ outer tube

Above examples are production. BTW, how about parallel chemistry?

According to the article, Abbie was developed SWIFT (synthesis with integrated flow technology, nice naming sense!). The system integrates flow reactor and HPLC/MS and be able to synthesize 6 pure compound per hour in 10 ~ 20mg scale! It is very productive I think. Even if I use parallel reactor such as miniblock, it is difficult to synthesis pure compounds such speed. Fig 24 shows SWIFT platform. It seems not so large. And there are some examples continuous synthesis and assay cycles. In Japan there are few examples of parallel chemistry with flow I think.

If we can run DMTA cycle within few hours, what will be task of medicinal chemists.