Molecular Docking and QSAR Studies of Coumarin Derivatives as NMT Inhibitors: Simple Structural Features as Potential Modulators of Antifungal Activity

Author(s): Sapna Jain Dabade, Dheeraj Mandloi*, Amritlal Bajaj

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 10 , 2020

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Graphical Abstract:


Background: Treatments of fungal diseases, including Candidiasis, remain not up to scratch in spite of the mounting catalog of synthetic antifungal agents. These have served as the impetus for investigating new antifungal agents based on natural products. Consequently, genetic algorithm-multiple linear regression (GA-MLR) based QSAR (Quantitative Structure-Activity Relationship) studies of coumarin analogues along with molecular docking were carried out.

Methods: Coumarin analogues with their MIC values were used to generate the training and test sets of compounds for QSAR models development; the analogues were also docked into the binding pocket of NMT (MyristoylCoA: protein N-myristoyltransferase).

Results and Discussion: The statistical parameters for internal and external validation of QSAR analysis (R2 = 0.830, Q2 = 0.758, R2Pred = 0.610 and R2m overall = 0.683 ), Y Randomization, Ridge trace, VIF, tolerance and model criteria of Golbraikh and Tropsha data illustrate the robustness of the best proposed QSAR model. Most of the analogues bind to the electrostatic, hydrophobic clamp and display hydrogen bonding with amino acid residues of NMT. Interestingly, the most active coumarin analogue (MolDock score of -189.257) was docked deeply within the binding pocket of NMT, thereby displaying hydrogen bonding with Tyr107, Leu451, Leu450, Gln226, Cys393 and Leu394 amino acid residues.

Conclusion: The combinations of descriptors from various descriptor subsets in QSAR analysis have highlighted the role of atomic properties such as polarizability and atomic van der Waals volume to explain the inhibitory activity. The models and related information may pave the way for important insight into the designing of putative NMT inhibitors for Candida albicans.

Keywords: QSAR, coumarin analogue, GA-MLR, molecular docking, Candida albicans, NMT inhibitors.

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Year: 2020
Published on: 12 October, 2020
Page: [1293 - 1308]
Pages: 16
DOI: 10.2174/1570180817999200617105711
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