Virologia e Micologia
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QM/MM Docking Strategy and Prime/MM-GBSA Calculation of Celecoxib Analogues as N-myristoyltransferase Inhibitors

Nisha Chandna, Kotni Meena Kumari, Chetan Sharma, Manga Vijjulatha, Jitander K. Kapoor and Pawan K. Sharma

Developing chemicals that inhibit N-myristoyltransferase (Nmt) is a promising adjuvant therapeutic to improve the
efficacy and selectivity of antifungal agents. Reliable prediction of binding-free energy and binding affinity of Nmt
inhibitors can provide a guide for rational drug design. In this study, Quantum Polarised Ligand Docking (QPLD)
strategy and Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA) calculations were
applied to predict the binding mode and free energy for a series of celecoxib analogues as Nmt inhibitors which
were also found to have good anti-inflammatory activity. In vitro antifungal assay indicated that these derivatives
were also acting as potent antifungal agents. Reliable docking results showed superior performance on both ligand
binding pose and docking score accuracy. Then, the Prime/MM–GBSA method based on the docking complex was
used to predict the binding-free energy. The combined use of QM/MM docking and Prime/MM-GBSA method gave a
good correlation between the predicted binding-free energy and experimentally determined zone of inhibition and
Minimum Inhibitory Concentration (MIC) values. The molecular docking combined with Prime/MM-GBSA simulation
can not only be used to rapidly and accurately predict the binding-free energy of novel Nmt inhibitors but also
provide a novel strategy for lead discovery and optimization targeting Nmt.