Discovery of Novel TASK-3 Channel Blockers Using a Pharmacophore-Based Virtual Screening

被引：16

作者：

Ramirez, David ^{[1
]}

Concha, Guierdy ^{[2
]}

Arevalo, Barbara ^{[3
]}

Prent-Penaloza, Luis ^{[4
,5
]}

Zuniga, Leandro ^{[2
]}

Kiper, Aytug K. ^{[6
]}

Rinne, Susanne ^{[6
]}

Reyes-Parada, Miguel ^{[7
,8
]}

Decher, Niels ^{[6
,9
,10
]}

Gonzalez, Wendy ^{[11
,12
]}

Caballero, Julio ^{[11
]}

机构：

[1] Univ Autonoma Chile, Fac Ciencias Salud, Inst Ciencias Biomed, El Llano Subercaseaux 2801,Piso 5, Santiago 8900000, Chile

[2] Univ Talca, Escuela Med, PIA CG, CIM, 2 Norte 685, Talca 3460000, Chile

[3] Univ Tecnol Chile Inacap, Informat & Telecomunicac, Sede Talca, Av San Miguel 3496, Talca 3460000, Chile

[4] Univ Talca, Inst Chem Nat Resources, Fac Engn, Organ Synth Lab,PhD Appl Sci, 1 Poniente 1141, Talca 3460000, Chile

[5] Univ Talca, Inst Chem Nat Resources, Fac Engn, Biol Act LSO Act Bio,PhD Appl Sci, 1 Poniente 1141, Talca 3460000, Chile

[6] Philipps Univ Marburg, Vegetat Physiol, Inst Physiol & Pathophysiol, Deutschhausstr 2, D-35037 Marburg, Germany

[7] Univ Santiago Chile, Fac Ciencias Med, Escuela Med, Ctr Invest Biomed & Aplicada CIBAP, Av Libertador Bernardo OHiggins 3677, Santiago 8900000, Chile

[8] Univ Autonoma Chile, Fac Ciencias Salud, Ave Pedro de Valdivia 425, Santiago 8900000, Chile

[9] Univ Marburg, CMBB, D-35037 Marburg, Germany

[10] Justus Liebig Univ Giessen, D-35037 Marburg, Germany

[11] Univ Talca, CBSM, 1 Poniente 1141, Talca 3460000, Chile

[12] Univ Talca, Millennium Nucleus Ion Channels Associated Dis Mi, Talca 3460000, Chile

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2019年 / 20卷 / 16期

关键词：

TASK-3; channel; drug design; TASK channels blockers; pharmacophore-based virtual screening; lead optimization; POTASSIUM CHANNELS; K+ CHANNEL; MOLECULAR DOCKING; CRYSTAL-STRUCTURE; BINDING; INHIBITORS; TRAAK; MEMBRANE; PORE; SITE;

D O I：

10.3390/ijms20164014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

TASK-3 is a two-pore domain potassium (K-2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 +/- 3.9 mu M. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 +/- 3.4 mu M. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.

引用

页数：22

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