ChemAIRS® manual search can make the synthesis of special small molecules more efficient

Date: 30.07.2022 By: Admin

As everyone knows, it will take 10 to 15 years and costs at least 1 billion dollars for an experimental drug after initial discovery to gain FDA approval, and needs to go through a series of research processes including vitro toxicity test, pre-clinical animal experiments, and clinical phase I, II, and III from initial discovery to ultimate approval. Nowadays, with the accelerated development of small molecule innovation drugs, various bio-active candidate molecules are continuously being synthesized. In recent decades, some pioneers containing new skeletons with high efficiency of drug activity have continuously been approved. New molecular skeleton drugs are the research direction of many pharmaceutical companies. In 2020, ACS Med. Chem. Lett. published a chemical article (DOI: org/10.1021/acsmedchem lett.0c00319), scientists have analyzed the skeleton of small molecule innovative drugs and provided some methods to discover the skeleton of innovation, but also pointed out that innovation of small molecule drugs is accelerating. The article analyzes 1089 small molecule innovative drugs (New Molecular Entities) that have been approved in the United States since 1938, and finds that the number of new framework molecular drugs containing new scaffolds (Pioneers) approved for marketing in the past 10 years has approached that of non-new molecules (Non-Pioneers), especially since this year, its growth rate has exceeded Non-Pioneers. The drug innovation based on structural novelty has an obvious relationship with whether the drug could achieve clinical and commercial success. The FDA states that drugs with chemically novelty are 2.5 times more likely to be considered as the breakthrough therapies than other drugs, and is 2 times more likely to be the blockbuster drugs.

For example, Risdiplam, reported in 2013, consists of three linked ring systems. The ring system shown in green (4, 7-Diazaspiro [2.5] Octane) is a spiral ring structure (composed of piperazine rings and ternary rings) that has not been seen in the chemical structure of previously approved drugs.

Selpercatinib is the first selective RET targeting drug approved by the FDA in 2018. The ring series shown in green (3, 6-diazacycle [3.1.1] heptane) has not been seen in the chemical structure of previously approved drugs.

Risdiplam (Left) and Selpercatinib (Right) molecular structure

These new skeletons play an increasingly important role in small molecule drug innovation. With the limitation of patent protection and the continuous increase of the cost of pharmaceutical research and development, it is the trend to screen out new skeletons active drug molecules, and the successful synthesis of these new framework molecules is an important link in the process. Especially for some skeletons with synthesis difficulties, chemists cannot give efficient synthesis ideas due to their limited experience. Therefore, artificial intelligence computer synthesis assistance will be an important tool in pharmaceutical research and development. ChemAIRS, developed by Chemical.AI, greatly saves time of route design by quickly giving chemists lots of synthetic ideas. ChemAIRS is an AI big data synthesis route design aid system launched by Chemical.AI for all users with organic synthesis needs. Through AI algorithm + big data, it can help enterprises realize digital informatization transformation and accelerate the efficiency of drug research and development. For molecules with known reported skeleton fragments, ChemAIRS can quickly provide known synthesis routes, while for unknown molecules, the predicted routes can be automatically searched or the desired routes can be found by manual derivation.

This topic will show how to perform synthetic route search for small molecule compounds through the manual derivation function of ChemAIRS. The following is a manual derivation procedure of the retrosynthesis for an unknown small molecule block (chiral diol compound).

Instruction: 1. input compound(CAS/Smiles/Sketchpad drawing), click “manual search”. 2. click the plus sigh “+” for organic synthesis derivation; 3. select the given intermediates, or click the plus sign to draw the desired intermediate; 4. click “show condition” or “change condition” to check the references, verify the feasibility of reaction.

The following six routes with synthetic reference value can be obtained through derivation. It can be found that: Route 1 is shorter; Route 2 is similar to route 1; In Route 3, raw material 1a may be polymerized; In Route 4, 1a is a known compound that is readily available; Route 5 is similar to Route 4, but the difference is the way of constructing three-membered ring. In Route 6, the by-products (trans structures) are inevitably formed. (The green box/green arrow is known compound/known reaction, CAS\Smiles\ References can be obtained by clicking on the green compound number, the purple box/purple arrow is unknown compound/unknown reaction).

Route 1

1a→2a:LDA,1,3,2-Dioxathiolane 2,2-dioxide,THF; 2a→3a:K2CO3,N2H4,diethylene glycol;3a→Target compound:K2OsO4,NMO,Pyridine,H2O/t-BuOH.

Route 2

1a→2a:US2418850(1944); 2a→3a:ZrCp2Cl2, EtMgBr, THF;3a→Target compound:K2OsO4,NMO,Pyridine,H2O/t-BuOH.

Route 3

1a→2a: CH2=C(CH3)CH2MgBr, THF; 2a→3a:Tos-OH; glycol; PhMe; 3a→4a: Grubbs 1st,DCM;4a→5a:HCl,H2O/THF; 5a→6a:ZrCp2Cl2, EtMgBr, THF; 6a→Target compound:K2OsO4,NMO,Pyridine,H2O/t-BuOH.

Route 4

1a→2a:K2OsO4,NMO,Pyridine,H2O/t-BuOH; 2a→3a:PPTS,Acetone;3a→4a:LiBH4, THF; 4a→5a:CBr4, TEA, PPh3, DCM; 5a→6a:Zn/EtOH; 6a→Target compound:HCl, H2O/THF.

Route 5

1a→2a:K2OsO4,NMO,Pyridine,H2O/t-BuOH; 2a→3a:PPTS,Acetone; 3a→4a:(Ph)3CH3P+Br-,t-BuOK, THF; 4a→5a:Et2Zn,THF; 5a→Target compound:HCl,H2O/THF.

Route 6

1a→2a:Na; TMSCl; PhMe; 2a→3a:HCl,THF; 3a→4a:CH3OPhCH2Br, Ag2O, CH3CN; 4a→5a:MeLi, THF; 5a→Target compound:DDQ,DCM.

It can be seen that six synthetic reference routes are derived by manual ChemAIRS derivation. Chemists can choose the intermediate given by the system during derivation, or they can draw the desired intermediate directly. Click the Show condition and Change conditions buttons to obtain references to verify the feasibility of the reaction. The ChemAIRS platform developed by Chemcal.AI offers a wide variety of references for users. Manual derivation simulates the process of retrosynthesis by chemists, which is unique in the market. With the continuous upgrade of algorithms and functions, ChemAIRS will provide maximum support for chemists in the future. It can not only recommend the algorithm synthesis routes to help users to obtain various synthesis ideas, but users can also combine their own synthesis experience to obtain the synthetic routes through manual derivation.

If you need more information or have extra requests, please contact bd@chemical.ai.