In –silico Study of 3-(2-amino-6-phenylpyrimidin-4-yl)-Ncyclopropyl-1-methyl-1H-indole-2-carboxamide derivatives as antifungal agents: CoMFA, CoMSIA analyses, Molecular Docking and ADMET Properties

Hanane Zaki, Assia Belhassan, Adnane Aouidat, Abdelali Taourati, Tahar Lakhlifi, Mohamed Benlyas, Mohammed Bouachrine

Abstract


Heterocyclic molecules manelly indoles derivatives have displayed a large diversity of biological activity profiles and many studies have focused mainly their therapeutic effect. It is noticed that the biological activity solidly depends on the kind and the location of the substituents in their molecules. The Multidimensional quantitative structure-activity/property relationship (Multidimensional QSAR/QSPR) method is used on this study, to study a series of 22 indole-pyrimidine. We have developed three-dimensional quantitative structure antifungal activity relationships for this series, using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) methods.
The results show a significant statistical quality and a satisfying predictive ability, with high correlation coefficient value (R2=0.922 and R2=0.876 for CoMFA and CoMSIA respectively). To validate the predictive power of the resulting models, external validation multiple correlation coefficient was calculated and we have noted a favorable estimation of stability for the two methods (Q2= 0.502 and Q2=0.530 for CoMFA and CoMSIA methods, respectively) On the other hand, docking study of the compound with highest activity has been performed to assess the interactions with sterol 14- alpha demethylase (CYP51) from Candida albicans. These interactions information between potential targets and ligand were presented such the useful theoretical references to understand the action mechanism of indole derivatives. Basing on CoMFAresults and molecular docking results new molecules candidates were designed and the ADMET proprieties were predicted to select the potential hits.


Keywords


3-(2-amino-6- phenylpyrimidin-4-yl)-N cyclopropyl-1-methyl-1H indole-2-carboxamide ; Antifungal activity ; Candida albicans ; Three-dimensional Quantitative structure activity relationship ; Comparative Molecular Field Analysis ; Comparative Molecular Sim

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Online ISSN: 2605-6895

Authors attest that their work is original and unpublished, and is not under consideration for publication elsewhere. In addition, authors confirm that their paper has not been copied or plagiarized, in whole or in part, from other works.