3D-QSAR, Pharmacophore Modeling, ADMET, and DFT Studies ofHalogenated Conjugated Dienones as Potent MAO-B Inhibitors

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dc.contributor.authorMathew, Githa Elizabeth
dc.contributor.authorHerrera-Acevedo, Chonny
dc.contributor.authorScotti, Marcus Tullius
dc.contributor.authorKumar, Sunil
dc.contributor.authorBerisha, Avni
dc.contributor.authorKaya, Savas
dc.contributor.authorAlfarraj, Saleh
dc.date.accessioned2024-10-26T18:11:24Z
dc.date.available2024-10-26T18:11:24Z
dc.date.issued2024
dc.departmentSivas Cumhuriyet Üniversitesi
dc.description.abstractIntroduction It has been reported that the extension of conjugation in chalcone scaffolds considerably enhanced the potency, selectivity, reversibility, and competitive mode of MAO-B inhibition. In this study, using the experimental results of IC50 values of fifteen halogenated conjugated dienone derivatives (MK1-MK15) against MAO-B, we developed a 3DQSAR model.Methods Further, we created a 3D pharmacophore model in active compounds in the series. The built model selected three variables (G2U, RDF115m, RDF155m) among the 653 AlvaDesc molecular descriptors, with a r2 value of 0.87 and a Q2 cv for cross-validation equal to 0.82. The three variables were mostly associated with the direction of symmetry and the likelihood of discovering massive atoms at great distances. The evaluated molecules exhibited a good correlation between experimental and predicted data, indicating that the IC50 value of the structure MK2 was related to the interatomic distances of 15.5 & Aring; between bromine and chloro substituents. Furthermore, the molecules in the series with the highest activity were those with enhanced second component symmetry directional index from the 3D representation, which included the structures MK5 and MK6.Results Additionally, a pharmacophore hypothesis was developed and validated using the decoy Schrodinger dataset, with an ROC score of 0.87 and an HHRR 1 fitness score that ranged from 2.783 to 3.00. The MK series exhibited a significant blood-brain barrier (BBB) permeability, according to exploratory analyses and in silico projections, and almost all analogues were expected to have strong BBB permeability.Conclusion Further DFT research revealed that electrostatics were important in the interactions with MAO-B.
dc.description.sponsorshipKing Saud University, Riyadh, Saudi Arabia [RSP2024R7]
dc.description.sponsorshipThis work was funded by Researchers Supporting Project number (RSP2024R7), King Saud University, Riyadh, Saudi Arabia.
dc.identifier.doi10.2174/0115734099307062240801053329
dc.identifier.issn1573-4099
dc.identifier.issn1875-6697
dc.identifier.pmid39129167
dc.identifier.scopus2-s2.0-85206087208
dc.identifier.urihttps://doi.org/10.2174/0115734099307062240801053329
dc.identifier.urihttps://hdl.handle.net/20.500.12418/30663
dc.identifier.wosWOS:001290695900001
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherBentham Science Publ Ltd
dc.relation.ispartofCurrent Computer-Aided Drug Design
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectMonoamine oxidase
dc.subjectconjugated dienone
dc.subject3D-QSAR
dc.subjectDFT
dc.title3D-QSAR, Pharmacophore Modeling, ADMET, and DFT Studies ofHalogenated Conjugated Dienones as Potent MAO-B Inhibitors
dc.typeArticle

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