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

Title:3D-QSAR, Pharmacophore Modeling, ADMET, and DFT Studies of Halogenated Conjugated Dienones as Potent MAO-B Inhibitors

Volume: 21 Issue: 2

Author(s): Githa Elizabeth Mathew, Chonny Herrera-Acevedo, Marcus Tullius Scotti, Sunil Kumar, Avni Berisha, Savaş Kaya, Saleh Alfarraj, Mohammad Javed Ansari, Archana Dhyani, Sachithra Thazhathuveedu Sudevan, Mohan Kumar and Bijo Mathew*

Affiliation:

• Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682041, India

Keywords: Monoamine oxidase, conjugated dienone, 3D-QSAR, DFT.

Abstract:

Introduction: 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 Å 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.

Result: 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.

Cite this article as:

Mathew Elizabeth Githa, Herrera-Acevedo Chonny, Scotti Tullius Marcus, Kumar Sunil, Berisha Avni, Kaya Savaş, Alfarraj Saleh, Ansari Javed Mohammad, Dhyani Archana, Sudevan Thazhathuveedu Sachithra, Kumar Mohan and Mathew Bijo*, 3D-QSAR, Pharmacophore Modeling, ADMET, and DFT Studies of Halogenated Conjugated Dienones as Potent MAO-B Inhibitors, Current Computer-Aided Drug Design 2025; 21 (2) . https://dx.doi.org/10.2174/0115734099307062240801053329