Computational Study of Potential MAO-B Inhibitors Based on 4-(3-Nitrophenyl) Thiazol-2-ylhydrazone.

Year 2025, , 129 - 156, 05.01.2025

Moulay Ahfid El Alaouy , Marwa Alaqarbeh , Mohamed Ouabane , Abdelouahid Sbai , Tahar Lakhlıfı , Mohammed Bouachrıne

https://doi.org/10.33435/tcandtc.1492847

Abstract

This study used a dataset comprising thirty-four derivatives of 4-(3-nitrophenyl) thiazol-2-ylhydrazone as selective monoamine oxidase B (h-MAO-B) inhibitors to design more effective h-MAO-B inhibitors. This was achieved by applying molecular modeling methods. Among the different field models examined, the CoMSIA/SEA model emerged as the most effective, compared to the other models (Q^2 = 0.60; R2 = 0.97; R^2test = 0.711; F = 151.84; SEE = 0.21; ONC = 4). Contour maps helped identify structural features important for inhibitory activity, leading to the design of four highly active inhibitors. The study explored the interaction between the new compounds (M1, M2, M3, and M4) and the most active molecule, No.3, using molecular docking simulations. This process revealed a positive interaction characterized by the formation of significant bonds with key protein residues such as Arg:42, Glu:58, Met:436, Tyr:398, Tyr:435, and Tyr:60. The ADMET properties of the predicted molecules (M1-M4) were generally favorable, except for molecule No.3, which retained its toxicity. Both M1 and the most active compound 3 underwent 100 ns molecular dynamics simulations, The results of these simulations indicate that the proposed molecule, M1, exhibits a slightly higher structural stability compared to the most active compound, 3. This positions M1 as a promising candidate for further studies. A retrosynthesis strategy was employed to efficiently plan the synthesis of molecule M1 as a potential MAO-B inhibitor, identifying the key steps and precursors required for its realization.

Keywords

thiazol-2-ylhydrazone., ADMET, 3D-QSAR, Molecular Modeling, hMAO-B

Ethical Statement

We, the undersigned, declare that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that all have approved the order of authors listed in the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions, and final approval of proofs

Supporting Institution

NA

Project Number

0000

Thanks

NA

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