School Of Basic And Applied Sciences

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    Identification of terpenoids as dihydropteroate synthase and dihydrofolate reductase inhibitors through structure-based virtual screening and molecular dynamic simulations
    (Taylor and Francis Ltd., 2023-05-13T00:00:00) Saini, Abhishek; Kumar, Amit; Jangid, Kailash; Kumar, Vinod; Jaitak, Vikas
    Bacterial infections are rising, and antimicrobial resistance (AMR) in bacteria has worsened the scenario, requiring extensive research to find alternative therapeutic agents. Terpenoids play an essential role in protecting plants from herbivores and pathogens. The present study was designed to focus on in silico evaluation of terpenoids for their affinity towards two necessary enzymes, i.e. DHFR and DHPS, which are involved in forming 5, 6, 7, 8-tetrahydrofolate, a key component in bacterial DNA synthesis proteins. Additionally, to account for activity against resistant bacteria, their affinity towards the L28R mutant of DHFR was also assessed in the study. The structure-based drug design approach was used to screen the compound library of terpenes for their interaction with active sites of DHFR and DHPS. Further, compounds were screened based on their dock score, pharmacokinetic properties, and binding affinities. A total of five compounds for each target protein were screened, having dock scores better than their respective standard drug molecules. CNP0169378 (?8.4 kcal/mol) and CNP0309455 (?6.5 kcal/mol) have been identified as molecules with a higher affinity toward the targets of DHFR and DHPS, respectively. At the same time, one molecule CNP0298407 (?5.8 kcal/mol for DHPS, ?7.6 kcal/mol for DHFR, ?6.1 kcal/mol for the L28R variant), has affinity for both proteins (6XG5 and 6XG4). All the molecules have good pharmacokinetic properties. We further validated the docking study by binding free energy calculations using the MM/GBSA approach and molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
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    Designing specific inhibitors against dihydrofolate reductase of W. bancrofti towards drug discovery for lymphatic filariasis
    (Springer, 2022-03-15T00:00:00) Sureshan, Muthusamy; Rajamanikandan, Sundarraj; Srimari, Srikanth; Prabhu, Dhamodharan; Jeyakanthan, Jeyaraman; Saraboji, Kadhirvel
    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.