Exploiting Structural Analysis, in Silico Screening, and Serendipity To Identify Novel Inhibitors of Drug-Resistant Falciparum Malaria (original) (raw)
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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.
Structure-based Design of Novel Small-Molecule Inhibitors of Plasmodium falciparum
Journal of Chemical Information and Modeling, 2010
Malaria is endemic in most developing countries, with nearly 500 million cases estimated to occur each year. The need to design a new generation of antimalarial drugs that can combat the most drugresistant forms of the malarial parasite is well recognized. In this study, we wanted to develop inhibitors of key proteins that form the invasion machinery of the malarial parasite. A critical feature of host-cell invasion by apicomplexan parasites is the interaction between the carboxy terminal tail of myosin A (MyoA) and the myosin tail interacting protein (MTIP). Using the co-crystal structure of the Plasmodium knowlesi MTIP and the MyoA tail peptide as input to the hybrid structure-based virtual screening approach, we identified a series of small molecules as having the potential to inhibit MTIP-MyoA interactions. Of the initial fifteen compounds tested, a pyrazole-urea compound inhibited P. falciparum growth with an EC 50 value of 145 nM. We screened an additional 51 compounds belonging to the same chemical class and identified eight compounds with EC 50 values less than 400 nM. Interestingly, the compounds appeared to act at several stages of the parasite's life cycle to block growth and development. The pyrazole-urea compounds identified in this study could be effective antimalarial agents because they competitively inhibit a key protein-protein interaction between MTIP and MyoA responsible for the gliding motility and invasive features of the malarial parasite.
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.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidinebased antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC 50 in the 28-695 lM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidinebased antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC 50 in the 28-695 lM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development.
Journal of Medicinal Chemistry, 2013
Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (Pf FAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the Pf FAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (Pf FabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with Pf FabI to identify their mode of binding and to confirm outcomes of docking simulations.
ACS Medicinal Chemistry Letters, 2018
The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of P. falciparum through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound BT1 from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.
Identification of three new inhibitor classes against Plasmodium falciparum
2022
In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-Dxylulose-5-phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities in the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of its antiparasitic action, displaying good cell-based activity for all classes. Through structure-activity relationship studies we increased their antimalarial potency, and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest intracellular polypharmacy. Similarity-based searches revealed two other possible target enzymes for this compound, which were further analyzed by docking calculations. All inhibitor classes are active against chloroquine resistant strains, confirming a new mode of action.
Pakistan journal of zoology
Advancement in computational biology leads to improve the efficacy for new compounds to cure the diseases. Malaria is the most virulent diseases and causing millions of deaths annually, especially in developing and underdeveloped countries. Plasmodium falciparum dihydrofolate reductase (PfDHFR) is one of the most important drug target for different antifolates. Pyrimethamine with sulphadoxine complex is the most recommended and efficient antifolate prescribed against PfDHFR. But malarial parasites have developed resistance against this drug due to the point mutations in PfDHFR. This study focus to design a novel antimalarial drug (analog) against mutated PfDHFR by considering the in silico approaches. The new antimalarial drugs were designed by the addition/substitution of different functional groups and molecules in parent compound of pyrimethamine. The docking studies of newly designed compound and pyrimethamine with mutated receptor protein of PfDHFR were performed by using different docking servers. Various in silico therapeutic calculations for novel antimalarial compound and pyrimethamine were executed using computational approaches. The basic of ligand properties, docking results, energy calculations and drug score favor indicated that the new antimalarial drug compound have potential to show better efficacy than pyrimethamine. This designed analog could be used for preclinical test and have the potential to eradicate P. falciparum.