Designing specific inhibitors against dihydrofolate reductase of W. bancrofti towards drug discovery for lymphatic filariasis

Abstract

Lymphatic filariasis (LF) is one among the leading neglected diseases caused by mosquitoe-borne parasite Wuchereria bancrofti to humans. Though drugs are available for the treatment of LF, all of which are not effective in all stages and moreover majority of these drugs have been reported with resistance. There is a need for effective new drugs which affect the parasite irrespective of its lifecycle and counter the drug resistance mechanisms. In the present study, we have explored the key enzyme dihydrofolate reductase (DHFR) as the potential target for developing drugs against LF. We have modelled dihydrofolate reductase structure and analysed its stability through the 200�ns simulation studies. Computer-assisted screening method found five non-toxic potent hit molecules with a docking score of ? 13.86 to ? 13.54�kcal/mol. Interestingly, we observed that the identified hit molecules are more specific to W. bancrofti DHFR than human DHFR due to electrostatic charge variations in the binding cavity. Higher specificity could increase the therapeutic efficacy and also minimize cross-reactivity with human targets. We have also found that the identified hit molecules have better glide score and energy than the reported DHFR inhibitors of W. bancrofti. Better score and energy values depict that the identified hit molecules could inhibit the DHFR activity efficiently. The DFT analysis predicted the regions in the hit molecules with higher probability of chemical reactivity and also potential sites to enhance the binding efficiency. Our findings provide new scaffolds for the development of DHFR inhibitors, which can be efficiently formulated to treat LF. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.