Exploration of potential RSK2 inhibitors by pharmacophore modelling, structure-based 3D-QSAR, molecular docking study and molecular dynamics simulation

Zhu, Xiaohong; Zhou, Lu; Zhong, Liangliang; Dai, Duoqian; Hong, Meiyuan; You, Rong; Wang, Taijin

doi:10.1080/08927022.2016.1274987

Cited by 3 publications

(1 citation statement)

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“…Consequently, 3D-QSAR averts this problem by using the 3D-attributes of ligands and chemometric tools. That significantly improves the predictability of the biological activity of the model [ 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies

Castro‐Alvarez

Chávez‐Ángel

Nelson

2021

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT4 receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT4 receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures’ field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R2training = 0.821, and for the test set R2test = 0.667, while for Gaussian-field QSAR the training and the test were R2training = 0.898 and R2test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q2LOO = 0.804 and Q2LOO = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT4 partial agonists with potential biological activity (pEC50 8.209–9.417 for force-field QSAR and 9.111–9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT4 partial agonists.

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