Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Carl A Machutta; Christopher S Kollmann; Kenneth E Lind; Xiaopeng Bai; Pan F Chan; Jianzhong Huang; Lluis Ballell; Svetlana Belyanskaya; Gurdyal S Besra; David Barros-Aguirre; Robert H Bates; Paolo A Centrella; Sandy S Chang; Jing Chai; Anthony E Choudhry; Aaron Coffin; Christopher P Davie; Hongfeng Deng; Jianghe Deng; Yun Ding; Jason W Dodson; David T Fosbenner; Enoch N Gao; Taylor L Graham; Todd L Graybill; Karen Ingraham; Walter P Johnson; Bryan W King; Christopher R Kwiatkowski; Joël Lelièvre; Yue Li; Xiaorong Liu; Quinn Lu; Ruth Lehr; Alfonso Mendoza-Losana; John Martin; Lynn McCloskey; Patti McCormick; Heather P O'Keefe; Thomas O'Keeffe; Christina Pao; Christopher B Phelps; Hongwei Qi; Keith Rafferty; Genaro S Scavello; Matt S Steiginga; Flora S Sundersingh; Sharon M Sweitzer; Lawrence M Szewczuk; Amy Taylor; May Fern Toh; Juan Wang; Minghui Wang; Devan J Wilkins; Bing Xia; Gang Yao; Jean Zhang; Jingye Zhou; Christine P Donahue; Jeffrey A Messer; David Holmes; Christopher C Arico-Muendel; Andrew J Pope; Jeffrey W Gross; Ghotas Evindar

doi:10.1038/ncomms16081

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Carl A Machutta, Christopher S Kollmann, Kenneth E Lind, Xiaopeng Bai, Pan F Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S Besra, David Barros-Aguirre, Robert H Bates, Paolo A Centrella, Sandy S Chang, Jing Chai, Anthony E Choudhry, Aaron Coffin, Christopher P Davie, Hongfeng Deng, Jianghe Deng, Yun DingJason W Dodson, David T Fosbenner, Enoch N Gao, Taylor L Graham, Todd L Graybill, Karen Ingraham, Walter P Johnson, Bryan W King, Christopher R Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P O'Keefe, Thomas O'Keeffe, Christina Pao, Christopher B Phelps, Hongwei Qi, Keith Rafferty, Genaro S Scavello, Matt S Steiginga, Flora S Sundersingh, Sharon M Sweitzer, Lawrence M Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P Donahue, Jeffrey A Messer, David Holmes, Christopher C Arico-Muendel, Andrew J Pope, Jeffrey W Gross, Ghotas Evindar

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Abstract

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Original language	English
Article number	16081
Journal	Nature Communications
Volume	8
Early online date	17 Jul 2017
DOIs	https://doi.org/10.1038/ncomms16081
Publication status	E-pub ahead of print - 17 Jul 2017

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Machutta, C. A., Kollmann, C. S., Lind, K. E., Bai, X., Chan, P. F., Huang, J., Ballell, L., Belyanskaya, S., Besra, G. S., Barros-Aguirre, D., Bates, R. H., Centrella, P. A., Chang, S. S., Chai, J., Choudhry, A. E., Coffin, A., Davie, C. P., Deng, H., Deng, J., ... Evindar, G. (2017). Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. Nature Communications, 8, Article 16081. Advance online publication. https://doi.org/10.1038/ncomms16081

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title = "Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening",

abstract = "The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.",

author = "Machutta, {Carl A} and Kollmann, {Christopher S} and Lind, {Kenneth E} and Xiaopeng Bai and Chan, {Pan F} and Jianzhong Huang and Lluis Ballell and Svetlana Belyanskaya and Besra, {Gurdyal S} and David Barros-Aguirre and Bates, {Robert H} and Centrella, {Paolo A} and Chang, {Sandy S} and Jing Chai and Choudhry, {Anthony E} and Aaron Coffin and Davie, {Christopher P} and Hongfeng Deng and Jianghe Deng and Yun Ding and Dodson, {Jason W} and Fosbenner, {David T} and Gao, {Enoch N} and Graham, {Taylor L} and Graybill, {Todd L} and Karen Ingraham and Johnson, {Walter P} and King, {Bryan W} and Kwiatkowski, {Christopher R} and Jo{\"e}l Leli{\`e}vre and Yue Li and Xiaorong Liu and Quinn Lu and Ruth Lehr and Alfonso Mendoza-Losana and John Martin and Lynn McCloskey and Patti McCormick and O'Keefe, {Heather P} and Thomas O'Keeffe and Christina Pao and Phelps, {Christopher B} and Hongwei Qi and Keith Rafferty and Scavello, {Genaro S} and Steiginga, {Matt S} and Sundersingh, {Flora S} and Sweitzer, {Sharon M} and Szewczuk, {Lawrence M} and Amy Taylor and Toh, {May Fern} and Juan Wang and Minghui Wang and Wilkins, {Devan J} and Bing Xia and Gang Yao and Jean Zhang and Jingye Zhou and Donahue, {Christine P} and Messer, {Jeffrey A} and David Holmes and Arico-Muendel, {Christopher C} and Pope, {Andrew J} and Gross, {Jeffrey W} and Ghotas Evindar",

year = "2017",

month = jul,

day = "17",

doi = "10.1038/ncomms16081",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer",

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Machutta, CA, Kollmann, CS, Lind, KE, Bai, X, Chan, PF, Huang, J, Ballell, L, Belyanskaya, S, Besra, GS, Barros-Aguirre, D, Bates, RH, Centrella, PA, Chang, SS, Chai, J, Choudhry, AE, Coffin, A, Davie, CP, Deng, H, Deng, J, Ding, Y, Dodson, JW, Fosbenner, DT, Gao, EN, Graham, TL, Graybill, TL, Ingraham, K, Johnson, WP, King, BW, Kwiatkowski, CR, Lelièvre, J, Li, Y, Liu, X, Lu, Q, Lehr, R, Mendoza-Losana, A, Martin, J, McCloskey, L, McCormick, P, O'Keefe, HP, O'Keeffe, T, Pao, C, Phelps, CB, Qi, H, Rafferty, K, Scavello, GS, Steiginga, MS, Sundersingh, FS, Sweitzer, SM, Szewczuk, LM, Taylor, A, Toh, MF, Wang, J, Wang, M, Wilkins, DJ, Xia, B, Yao, G, Zhang, J, Zhou, J, Donahue, CP, Messer, JA, Holmes, D, Arico-Muendel, CC, Pope, AJ, Gross, JW & Evindar, G 2017, 'Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening', Nature Communications, vol. 8, 16081. https://doi.org/10.1038/ncomms16081

TY - JOUR

T1 - Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

AU - Machutta, Carl A

AU - Kollmann, Christopher S

AU - Lind, Kenneth E

AU - Bai, Xiaopeng

AU - Chan, Pan F

AU - Huang, Jianzhong

AU - Ballell, Lluis

AU - Belyanskaya, Svetlana

AU - Besra, Gurdyal S

AU - Barros-Aguirre, David

AU - Bates, Robert H

AU - Centrella, Paolo A

AU - Chang, Sandy S

AU - Chai, Jing

AU - Choudhry, Anthony E

AU - Coffin, Aaron

AU - Davie, Christopher P

AU - Deng, Hongfeng

AU - Deng, Jianghe

AU - Ding, Yun

AU - Dodson, Jason W

AU - Fosbenner, David T

AU - Gao, Enoch N

AU - Graham, Taylor L

AU - Graybill, Todd L

AU - Ingraham, Karen

AU - Johnson, Walter P

AU - King, Bryan W

AU - Kwiatkowski, Christopher R

AU - Lelièvre, Joël

AU - Li, Yue

AU - Liu, Xiaorong

AU - Lu, Quinn

AU - Lehr, Ruth

AU - Mendoza-Losana, Alfonso

AU - Martin, John

AU - McCloskey, Lynn

AU - McCormick, Patti

AU - O'Keefe, Heather P

AU - O'Keeffe, Thomas

AU - Pao, Christina

AU - Phelps, Christopher B

AU - Qi, Hongwei

AU - Rafferty, Keith

AU - Scavello, Genaro S

AU - Steiginga, Matt S

AU - Sundersingh, Flora S

AU - Sweitzer, Sharon M

AU - Szewczuk, Lawrence M

AU - Taylor, Amy

AU - Toh, May Fern

AU - Wang, Juan

AU - Wang, Minghui

AU - Wilkins, Devan J

AU - Xia, Bing

AU - Yao, Gang

AU - Zhang, Jean

AU - Zhou, Jingye

AU - Donahue, Christine P

AU - Messer, Jeffrey A

AU - Holmes, David

AU - Arico-Muendel, Christopher C

AU - Pope, Andrew J

AU - Gross, Jeffrey W

AU - Evindar, Ghotas

PY - 2017/7/17

Y1 - 2017/7/17

N2 - The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

AB - The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

U2 - 10.1038/ncomms16081

DO - 10.1038/ncomms16081

M3 - Article

C2 - 28714473

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 16081

ER -

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Abstract

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