TY - JOUR
T1 - Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors
AU - Mellado, Marco
AU - González, César
AU - Mella, Jaime
AU - Aguilar, Luis F.
AU - Viña, Dolores
AU - Uriarte, Eugenio
AU - Cuellar, Mauricio
AU - Matos, Maria J.
N1 - Funding Information:
The authors thanks to Dr. Carlos Echiburu-Chau for the collection and identification of S. graveolens. MM thanks Agencia Nacional de Investigaci?n y Desarrollo (ANID, Chile, Fondecyt Postdoctoral Grant 3180408). MJM thanks Xunta de Galicia (Galician Plan of Research, Innovation and Growth 2011?2015, Plan I2C, ED481B 2014/086?0 and ED481B 2018/007) and Funda??o para a Ci?ncia e Tecnologia (FCT, CEECIND/02423/2018 and UIDB/00081/2020). Authors would like to thank Prof. Lourdes Santana for her scientific support.
Funding Information:
The authors thanks to Dr. Carlos Echiburu-Chau for the collection and identification of S. graveolens. MM thanks Agencia Nacional de Investigación y Desarrollo (ANID, Chile, Fondecyt Postdoctoral Grant 3180408). MJM thanks Xunta de Galicia (Galician Plan of Research, Innovation and Growth 2011–2015, Plan I2C, ED481B 2014/086–0 and ED481B 2018/007) and Fundação para a Ciência e Tecnologia (FCT, CEECIND/02423/2018 and UIDB/00081/2020). Authors would like to thank Prof. Lourdes Santana for her scientific support.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151–173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was −10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure–activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.
AB - Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151–173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was −10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure–activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.
KW - 3D-QSAR models
KW - Chalcone derivatives
KW - Drug design
KW - Molecular docking
KW - Monoamine oxidase B inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85100511879&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2021.104689
DO - 10.1016/j.bioorg.2021.104689
M3 - Article
AN - SCOPUS:85100511879
VL - 108
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
SN - 0045-2068
M1 - 104689
ER -