TY - JOUR
T1 - Designed spiroketal protein Modulation
AU - Scheepstra, M.
AU - Andrei, S.A.
AU - Unver, M Y.
AU - Hirsch, A.K.H.
AU - Leysen, S.
AU - Ottmann, C.
AU - Brunsveld, L.
AU - Milroy, L.-G.
N1 - © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
PY - 2017/5/8
Y1 - 2017/5/8
N2 - Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure-based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co-activator recruitment. We solved the crystal structure of the spiroketal-hRXRα-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co-crystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.
AB - Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure-based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co-activator recruitment. We solved the crystal structure of the spiroketal-hRXRα-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co-crystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.
KW - drug design
KW - drug discovery
KW - natural products
KW - spiro compounds
KW - structure elucidation
UR - http://www.scopus.com/inward/record.url?scp=85017467746&partnerID=8YFLogxK
U2 - 10.1002/anie.201612504
DO - 10.1002/anie.201612504
M3 - Article
C2 - 28407400
VL - 56
SP - 5480
EP - 5484
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 0570-0833
IS - 20
ER -