Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles

被引：52

作者：

Williamson, Alice E. ^{[1
]}

Ylioja, Paul M. ^{[1
]}

Robertson, Murray N. ^{[1
]}

Antonova-Koch, Yevgeniya ^{[2
]}

Avery, Vicky ^{[3
]}

Baell, Jonathan B. ^{[4
]}

Batchu, Harikrishna ^{[5
]}

Batra, Sanjay ^{[5
]}

Burrows, Jeremy N. ^{[6
]}

Bhattacharyya, Soumya ^{[5
]}

Calderon, Felix ^{[7
]}

Charman, Susan A. ^{[4
]}

Clark, Julie ^{[8
]}

Crespo, Benigno ^{[7
]}

Dean, Matin ^{[1
]}

Debbert, Stefan L. ^{[9
]}

Delves, Michael ^{[10
]}

Dennis, Adelaide S. M. ^{[11
]}

Deroose, Frederik ^{[12
]}

Duffy, Sandra ^{[3
]}

Fletcher, Sabine ^{[3
]}

Giaever, Guri ^{[13
]}

Hallyburton, Irene ^{[14
]}

Gamo, Francisco-Javier ^{[7
]}

Gebbia, Marinella ^{[13
]}

Guy, R. Kiplin ^{[8
]}

Hungerford, Zoe ^{[1
]}

Kirk, Kiaran ^{[11
]}

Lafuente-Monasterio, Maria J. ^{[7
]}

Lee, Anna ^{[13
]}

Meister, Stephan ^{[2
]}

Nislow, Corey ^{[13
]}

Overington, John P. ^{[15
]}

Papadatos, George ^{[15
]}

Patiny, Luc ^{[16
]}

Pham, James ^{[17
]}

Ralph, Stuart A. ^{[17
]}

Ruecker, Andrea ^{[10
]}

Ryan, Eileen ^{[4
]}

Southan, Christopher ^{[18
]}

Srivastava, Kumkum ^{[5
]}

Swain, Chris ^{[19
]}

Tarnowski, Matthew J. ^{[1
]}

Thomson, Patrick ^{[20
]}

Turner, Peter ^{[1
]}

Wallace, Iain M. ^{[15
]}

Wells, Timothy N. C. ^{[6
]}

White, Karen ^{[4
]}

White, Laura ^{[1
]}

Willis, Paul ^{[6
]}

机构：

[1] Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia

[2] Univ Calif San Diego, Dept Pediat Pharmacol & Drug Dev, 9500 Gilman Dr, La Jolla, CA 92093 USA

[3] Griffith Univ, Eskitis Inst Drug Discovery, Discovery Biol, Nathan, Qld 4111, Australia

[4] Monash Univ, Monash Inst Pharmaceut Sci, 381 Royal Parade, Parkville, Vic 3052, Australia

[5] CSIR Cent Drug Res Inst, Sect 10, Sitapur Rd, Lucknow 226031, Uttar Pradesh, India

[6] Med Malaria Venture, POB 1826,20 Rte Prebois, CH-1215 Geneva 15, Switzerland

[7] GlaxoSmithKline, Dis Dev World, Tres Cantos Medicines Dev Campus,Severo Ochoa 2, Tres Cantos 28760, Spain

[8] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, MS 1000,Room E9050,262 Danny Thomas Pl, Memphis, TN 38105 USA

[9] Lawrence Univ, Dept Chem, 233 Steitz Sci Hall,711 East Boldt Way, Appleton, WI 54911 USA

[10] Imperial Coll London, Dept Life Sci, London SW7 2AZ, England

[11] Australian Natl Univ, Res Sch Biol, Canberra, ACT 2601, Australia

[12] Asclepia Outsourcing Solut, Damvalleistr 49, B-9070 Destelbergen, Belgium

[13] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, 160 Coll St, Toronto, ON M5S 3E1, Canada

[14] Univ Dundee, Div Biol Chem & Drug Discovery, Drug Discovery Unit, Dundee DD1 5EH, Scotland

[15] European Mol Biol Lab, European Bioinformat Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England

[16] Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn ISIC, CH-1015 Lausanne, Switzerland

[17] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia

[18] Univ Edinburgh, Sch Biomed Sci, Ctr Integrat Physiol, IUPHAR BPS Guide PHARMACOLOGY, Edinburgh EH8 9XD, Midlothian, Scotland

[19] Cambridge MedChem Consulting, 8 Mangers Lane, Cambridge CB22 4RN, England

[20] Univ Edinburgh, Sch Chem, Joseph Black Bldg,West Mains Rd, Edinburgh EH9 3JJ, Midlothian, Scotland

[21] Swiss Trop & Publ Hlth Inst, Socinstr 57, CH-4051 Basel, Switzerland

来源：

ACS CENTRAL SCIENCE | 2016年 / 2卷 / 10期

基金：

澳大利亚研究理事会; 英国医学研究理事会; 英国惠康基金;

关键词：

OPEN-SOURCE SOFTWARE; PLASMODIUM-FALCIPARUM; SPIROINDOLONE ANTIMALARIALS; CYCLOPROPYL CARBOXAMIDES; MEDICINAL CHEMISTRY; TROPICAL DISEASES; MALARIA PARASITE; STARTING POINTS; OPEN INNOVATION; TARGET;

D O I：

10.1021/acscentsci.6b00086

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

引用

页码：687 / 701

页数：15

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