A vending machine for drug-like molecules - automated synthesis of virtual screening hits

被引：6

作者：

McMillan, Angus E. ^{[1
]}

Wu, Wilson W. X. ^{[1
]}

Nichols, Paula L. ^{[1
,2
]}

Wanner, Benedikt M. ^{[2
]}

Bode, Jeffrey W. ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Lab Organ Chem, CH-8093 Zurich, Switzerland

[2] Synple Chem AG, Kemptpk 18, CH-8310 Kemptthal, Switzerland

来源：

CHEMICAL SCIENCE | 2022年 / 13卷 / 48期

关键词：

DISCOVERY;

D O I：

10.1039/d2sc05182f

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large "on-demand" virtual libraries (>7 x 10(12) members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans. In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries.

引用

页码：14292 / 14299

页数：8

共 50 条

[1] Screening molecules for their drug-like index.
Rayan, A
Scaiewicz, A
Geva-Dotan, I
Barasch, D
Goldblum, A
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2004, 228 : U358 - U358
[2] Synthesis of new penicillin derivatives as drug-like molecules for biological screening
Chun-Jing Liu
Dinah Dutta
Lester Mitscher
[J]. Chinese Chemical Letters, 2015, 26 (01) : 113 - 117
[3] Synthesis of new penicillin derivatives as drug-like molecules for biological screening
Liu, Chun-Jing
Dutta, Dinah
Mitscher, Lester
[J]. CHINESE CHEMICAL LETTERS, 2015, 26 (01) : 113 - 117
[4] Generative Network Complex for the Automated Generation of Drug-like Molecules
Gao, Kaifu
Duc Duy Nguyen
Tu, Meihua
Wei, Guo-Wei
[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2020, 60 (12) : 5682 - 5698
[5] Catalysis in aqueous media for the synthesis of drug-like molecules
Lombardo, Marco
Trombini, Claudio
[J]. CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, 2010, 13 (06) : 717 - 732
[6] Modeling quinone formation of drug-like molecules with machine learning
Hughes, Tyler B.
Le Dang, Na
Swamidass, S. Joshua
[J]. DRUG METABOLISM REVIEWS, 2016, 48 : 107 - 107
[7] Modeling Epoxidation of Drug-like Molecules with a Deep Machine Learning Network
Hughes, Tyler B.
Miller, Grover P.
Swamidass, S. Joshua
[J]. ACS CENTRAL SCIENCE, 2015, 1 (04) : 168 - 180
[8] Modeling epoxidation of drug-like molecules with a deep machine learning network
Swamidass, S. Joshua
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 251
[9] Discovery of a New Drug-like Series of OGT Inhibitors by Virtual Screening
Loi, Elena M.
Tomasic, Tihomir
Balsollier, Cyril
van Eekelen, Kevin
Weiss, Matjaz
Gobec, Martina
Alteen, Matthew G.
Vocadlo, David J.
Pieters, Roland J.
Anderluh, Marko
[J]. MOLECULES, 2022, 27 (06):
[10] Tautomerization approach for drug-like molecules
Shelley, John C.
Sullivan, Arron P.
Calkins, David
Greenwood, Jeremy R.
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2010, 240

← 1 2 3 4 5 →