Molecular modeling and binding interaction analysis of coumarin oxime ether derivatives against mycobacterial dihydrofolate reductase

Tuberculosis (TB) is a life-threatening disease and remains a serious health issue worldwide. The situation has become worse due to the developing multi-drug resistance (MDR) of antibiotics towards Mycobacterium tuberculosis (Mtb) strains. Antimicrobial drugs are available for the treatment of TB, however, drug toxicity, poor absorption of drugs, slow drug action, and drug resistance are some of the factors causing the threatening progress of the infection. Hence, developing a new strategy or a potent therapeutic agent has become an urgent need to counter the globally occurring TB epidemic. Previous studies showed that the coumarin-oxime derivatives as the potential inhibitors for various metabolic enzymes in Mtb. In our present study, we performed a comparative study on Mycobacterial Dihydrofolate Reductase (mDHFR) and Human Dihydrofolate Reductase (hDHFR), as potential drug targets. We carried out the virtual screening of the coumarin-oxime ether derivatives. Using an in-silico structure-based drug designing approach, the differences in binding energies of the substrate and inhibitor were determined between target sites of mycobacterium tuberculosis (Mtb) and human to design a drug molecule against Mycobacterium. Accelrys Discovery Studio version 3.0 was employed for ADMET analysis. Additionally, a protein-protein interaction network was generated for both the proteins using the STRING database. The MD simulation study, suggested that 1 g and 1f are the potential compounds, and were found to be in the top five hits for all the target proteins. Additionally, DFT study showed that the leading compounds has the highest CDOCKER interaction energy with mDHFR.