b74ea09be2e4404d41b959f617ffde47 pmc_33808456.pdf 5a036e77a44cdd772fcefc460f1d7db33851329e pmc_33808456.pdf 604ba37008861cf1abf25457c43e46303ec2e94e6b6f730aa470d10f167c01d1 pmc_33808456.pdf Title: Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies Subject: 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. Keywords: Alzheimer’s disease; 5-HT4; partial agonist; 3D-QSAR; force and gaussian fields Author: Alejandro Castro-Alvarez, Emigdio Chávez-Ángel and Ronald Nelson Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Mar 30 15:53:05 2021 CEST ModDate: Fri Apr 9 05:19:34 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4124471 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CBKAWJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 NBEGLK+VnURWPalladioL Type 1 Custom yes yes no 15 0 SIUZVB+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 GDXOXC+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 XTXCWC+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 36 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EDJBEB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 744 0 EDJEDA+Arial CID TrueType Identity-H yes yes yes 747 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:24:20 CEST RepresentationInformation: pmc_33808456.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:09:34 CEST Size: 4124471 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 981 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results and Discussion Destination: section.2 Children: Item: Title: Studied Compounds Destination: subsection.2.1 Item: Title: Statistical Results Destination: subsection.2.2 Item: Title: Analysis of the 3D-QSAR Models Destination: subsection.2.3 Children: Item: Title: Force-Field Based 3D-QSAR Model Steric and Electrostatic Contour Map Destination: subsubsection.2.3.1 Item: Title: Gaussian-Field Based 3D-QSAR Model Steric Contour Map Destination: subsubsection.2.3.2 Item: Title: Gaussian-Field Based 3D-QSAR Model Electrostatic Contour Map Destination: subsubsection.2.3.3 Item: Title: Gaussian-Field Based 3D-QSAR Model Hydrogen Bond Acceptor Contour Maps Destination: subsubsection.2.3.4 Item: Title: Gaussian-Field Based 3D-QSAR Model Hydrogen Bond Donor Contour Maps Destination: subsubsection.2.3.5 Item: Title: Design of New Derivatives Destination: subsection.2.4 Item: Title: ADMET Predictions Destination: subsection.2.5 Item: Title: Materials and Methods Destination: section.3 Children: Item: Title: Dataset Collection Destination: subsection.3.1 Item: Title: Alignment Destination: subsection.3.2 Item: Title: Field-Based QSAR Model Destination: subsection.3.3 Item: Title: Prediction ADMET Properties Destination: subsection.3.4 Item: Title: Conclusions Destination: section.4 Item: Title: References Destination: figure.caption.17 Info: Title: Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies Author: Alejandro Castro-Alvarez, Emigdio Chávez-Ángel and Ronald Nelson Subject: 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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