Rational design of novel sirtuin 1 activators via structure-activity insights from application of QSAR modeling
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Date
2019-04-05
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Abstract
Sirtuin 1 (SIRT1) enzyme regulates major cell activities, and its activation offers lucrative therapeutic potentials
for aging diseases including Alzheimer’s disease (AD). Regarding the global aging society, continual attention has
been given to various chemical scaffolds as a source for the discovery of novel SIRT1 activators since the discovery
of the pioneer activator, resveratrol. Understanding structure-activity relationship (SAR) is essential for screening,
designing as well as improving the properties of drugs. In this study, an in silico approach based on quantitative
structure-activity relationship (QSAR) modeling, was employed for understanding the SAR of currently available
SIRT1 fused-aromatic activators (i.e., imidazothiazole, oxazolopyridine, and azabenzimidazole analogs). Three
QSAR models constructed using multiple linear regression (MLR) provided good predictive performance (R2
LOOCV
= 0.729 - 0.863 and RMSELOOCV = 0.165 - 0.325). An additional novel set of 181 structurally modified compounds
were rationally designed according to key descriptors deduced from the QSAR findings and their SIRT1 activities
were predicted using the constructed models. In overview, the study provides insightful SAR findings of currently
available SIRT1 activators that would be useful for guiding the rational design, screening, and development of
further potent SIRT1 activators for managing age-related clinical conditions. A series of promising compounds as
well as important scaffolds and molecular properties for potent SIRT1 activator were highlighted. This study
demonstrated the efficacious role of QSAR-driven structural modification for the rational design of novel leads.
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Keywords
Sirtuin 1 activator, Aging disease, Alzheimer’s disease, QSAR, Drug design, Structural modification, Cheminformatics