Identification of novel dihydrofolate reductase inhibitor as potential antimalarial drug. Pakistan J. Zool., 46: 1263-1270 (original) (raw)
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DHFR from Pf is a known target for malaria. There is a continued effort for the design and development of the potent inhibitor for PfDHFR in the control of malaria. Therefore it is of interest to screen PfDHFR with the derivatives of Pyrimethamine. The results show that the compound CID 10476801 has lowest docked energy (-11.48 kcal/mol) with protein likely to be a drug candidate, probably inhibiting PfDHFR structure. Residues of PfDHFR protein involved in the formation of hydrogen bonds with compound CID 10476801 are confirmed to be ASP54. The findings provide new insights into development of potent chemotherapeutic drug for combating malaria.
Journal of Proteomics & Bioinformatics, 2014
Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) function is effectively inhibited by antifolates. The binding affinity of antifolates to PfDHFR-TS is reduced due to mutations in its active site. In the present study, 33 analogues of Methotrexate (MTX), Trimetrexate (TMX), Raltitrexed (RTX) and Pemetrexed (PTX) were designed and evaluated for interaction with PfDHFR-TS by in silico methods. Analyses of drug candidates were performed by generating their docking complexes with quadruple mutant crystal structure of PfDHFR-TS using Molecular Operating Environment (MOE). Initially eight top scoring complexes and then finally two (MTX04 and PTX03) were found suitable for further optimization based on interaction pattern with active site amino acids. Analyses of structural characteristics, binding energy calculations and interaction patterns of MTX04 and PTX03 with DHFR and TS domains respectively as best drug candidates. The comparative docking studies of these two compounds with human proteins provided a strong evidence of selectivity for MTX04 as effective antimalarial drug candidate. It is considered that the drug will inhibit the activity of folate pathway and it will be effective source to control malaria.
Tropical Journal of Natural Product Research (TJNPR), 2024
Plasmodium falciparum dihydrofolate reductase (PfDHFR) is an essential enzyme in the development of parasitic DNA and its inhibition often leads to the impediment of parasite growth. Several studies have also shown that a genetic mutation in this enzyme can cause reduced receptor responsiveness and efficacy of antimalarial drugs. Therefore, this study aimed to examine 100 compounds derived from Indonesian medicinal plants as potential antimalarial candidates using a structure-based virtual screening approach. The PASS online was used to screen 100 compounds, and those with Pa values higher than 0.3 were docked with the wild-type (PDB code:1j3i) and quadrupole mutant PfDHFR (PDB code:1j3k). The stability of the chemical complex was then examined using molecular dynamics simulations, followed by an assessment of the pharmacokinetic profile and drug-likeness parameters. The top 5 compounds were then identified with binding energies ranging from-9.7 to-10.0 kcal/mol for the wild-type PfDHFR-TS and from-9.2 to-10.0 kcal/mol for the quadrupole mutant PfDHFR. The results showed that compound C90 exhibited the most stable and impressive score in its pharmacokinetic and drug-likeness assessment.
2015
Malaria is one of the most common diseases caused by protozoa of the genus Plasmodium in tropical countries. Plasmodium falciparum dihydrofolate reductase (pfDHFR) is essential for parasite growth and has been validated as an antimalarial drug target for development of new Antifolate antimalarial agents. In this study, we have used 22 known Pyrimidine inhibitors of pfDHODH were used for building 2D QSAR model using linear regression analysis with five variables (descriptors) namely Binding energy, Intermol Energy, Torsional Energy, Internal Energy and Docking Energy, which are computed by AutoDock 3.0.5 tool. The observed and predicted biological activities of the molecules are reported. The results obtained from this study were used in predicting activities in terms of pKi value of Pyrimidine derivatives. This methodology allows the identification of probable lead candidates expeditiously prior to chemical synthesis and characterization and is more cost effective. KeywordsMalaria, ...
Journal of Molecular Graphics and Modelling, 2013
Plasmodium falciparum causes the most fatal form of malaria and accounts for over 1 million deaths annually, yet currently used drug therapies are compromised by resistance. The malaria parasite cannot salvage pyrimidines and relies on de novo biosynthesis for survival. The enzyme dihydrooratate dehydrogenase (DHODH), a mitochondrial flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive anti-malarial chemotherapeutic target. In an effort to design new and potential anti-malarials, structure-based pharmacophore mapping, molecular docking, binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to design new and potent P. falciparum dihydrooratate dehydrogenase (PfDHODH) inhibitors. A structure-based pharmacophore model was generated which consist of important interactions as observed in co-crystal of PfDHODH enzyme. The developed model was used to retrieve molecules from ChemBridge database, a freely available commercial database. A total of 87 molecules mapped on the modeled pharmacophore from the database. The retrieved hits were further screened by docking simulation, binding energy calculations and biding affinity predictions using genetic optimization for ligand docking (GOLD) and MOE. Based on these results, finally 26 chemo-types molecules were predicted as new, potential and structurally diverse PfDHODH inhibitors.
Bioinformation, 2020
Malaria remains a global public health burden with significant mortality and morbidity. Despite the several approved drugs available for its management, the parasite has developed resistance to virtually all known antimalarial drugs. The development of a new drug that can combat resistant to Artemisinin based Combination Therapies (ACTs) for malaria is imperative. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a flavin-dependent mitochondrial enzyme is vital in the parasite's pyrimidine biosynthesis is a well-known drug target. Therefore, it is of interest to document the MOLECULAR DOCKING analysis (using Maestro, Schrodinger) data of DIHYDROOROTATE DEHYDROGENASE PfDHODH from P. falciparum towards the design of effective inhibitors. The molecular docking features of 10 compounds with reference to chloroquine with PfDHODH are documented in this report for further consideration.
Research Journal of Pharmacy and Technology, 2018
Plasmodium falciparum causes the most fatal form of malaria and accounts for over 1 million deaths annually, yet currently used drug therapies are compromised by resistance. The malaria parasite cannot salvage pyrimidines and relies on de novo biosynthesis for survival. The enzyme dihydrooratate dehydrogenase (DHODH), a mitochondrial flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive anti-malarial chemotherapeutic target. In an effort to design new and potential anti-malarials, structure-based pharmacophore mapping, molecular docking, binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to design new and potent P. falciparum dihydrooratate dehydrogenase (PfDHODH) inhibitors. A structure-based pharmacophore model was generated which consist of important interactions as observed in co-crystal of PfDHODH enzyme. The developed model was used to retrieve molecules from ChemBridge database, a freely available commercial database. A total of 87 molecules mapped on the modeled pharmacophore from the database. The retrieved hits were further screened by docking simulation, binding energy calculations and biding affinity predictions using genetic optimization for ligand docking (GOLD) and MOE. Based on these results, finally 26 chemo-types molecules were predicted as new, potential and structurally diverse PfDHODH inhibitors.
Bioorganic & Medicinal Chemistry, 2010
The triazolo[4,3-a]pyrazin analogues are of interest due to their potential activity against various infectious and non-infectious disease. In search of suitable potent drug candidate, we report here the design, synthesis, characterization, biological activities and computation study of novel triazolo[4,3-a]pyrazin analogues. The synthesized molecules were characterized by various spectroscopic studies such as IR, Mass, 1 H-NMR, 13 C-NMR and elemental analysis. The newly synthesized compounds were evaluated for their in vitro biological activities such as anti-malarial, anti-tuberculosis, anti-bacterial and anti-fungal activities against plasmodium falciparum, H 37 Rv, various bacterial and fungal strains, respectively. The molecular docking study was carried out with enzyme aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum to analyze their binding orientation in the active site of the aspartic proteinase enzyme. The best docking complex was subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. We have also calculated ADMET properties of all the synthesized compounds to predict the pharmacokinetic properties for the selection of the active and bioavailability of compounds.