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Molecular Docking of Selective Binding Affinity of Sulfonamide Derivatives as Potential Antimalarial Agents Targeting the Glycolytic Enzymes: GAPDH, Aldolase and TPI

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Open Journal of Biophysics 2017年第1期7卷 41-57页

作者： neville forlemu Porshaye Watkins Joseph Sloop School of Science & Technology (Chemistry) Georgia Gwinnett College 1000 University Center Lane Lawrenceville GA USA

The parasite Plasmodium falciparum is responsible for the major world scourge malaria, a disease that affects 3.3 billion people worldwide. The development of new drugs is critical because of the diminished effectiveness of current antimalarial agents mainly due to parasitic resistance, side effects and cost. Molecular docking was used to explore structural motifs responsible for the interactions between triose phosphate isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and aldolase (ALD) from human and Plasmodium cells with 8 novel sufonylamide derivatives. All the ligands modeled, interact with all three enzymes in the micromolar range. The top ligand (sulfaE) shows a 70-fold increase in selective binding to pfTPI compared to hTPI (dissociation constant-KI of 7.83 μM and 0.177 μM for hTPI and pfTPI respectively), on par with antimalarial drug *** and GAPDH form complexes with similar binding sites, comprising amino acids of similar chemical properties and polarities. Human TPI and pfTPI bind sulfonamide derivatives using two distinct binding sites and residues. Key residues at the dimer interface of pfTPI (VAL44, SER45, TYR48, GLN64, ASN65, VAL78) form a tight pocket with favorable polar contacts. The affinity with TPI is the most specific, stable, and selective suggesting pfTPI is a candidate for development of antimalarial drugs.

关键词： Malaria Glycolytic Enzymes AutoDock4.2 Dissociation Constant Triosephosphate Isomerase Binding Affinity

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Computational Study of the Interactions between Antimalarial Chemotherapies with Folate Pathway Receptors and Telomerase Reverse Transcriptase

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Computational Chemistry 2021年第3期9卷 197-214页

作者： Djogang Lucie Karelle forlemu neville Emadak Alphonse Njabon Njankwa Eric Issofa Patouossa Nenwa Justin Physical and Theoretical Chemistry Laboratory Faculty of Science University of Yaounde I Yaounde Cameroon Applied Inorganic Chemistry Laboratory Faculty of Science University of Yaounde I Yaounde Cameroon School of Science & Technology (Chemistry) Georgia Gwinnett College Lawrenceville USA

Malaria is a life-threatening disease responsible for half a million death annually, and with nearly half of the world’s population at risk. The rapid drop in observed cases of malaria in the last two decades has been due to a combination of preventive and therapeutic remedies. However, the absence of a vaccine, new antimalarial chemotherapies and increased parasitic resistance have led to a plateau of infections and renewed research interest in target human and Plasmodium (the malaria parasite) receptors and new drugs. In this study, the impact of mutation on the affinity on antimalarial drugs with the bifunctional enzyme complex, dihydrofolate reductase (DHFR) is explored. In addition, homology modeling is used to build the three-dimensional models of the enzymes Plasmodium telomerase reverse-transcriptase (pf-TERT) and Plasmodium dihydropteroate synthetase (pf-DHPS) to determine their affinity with antimalarial drugs. The interaction energies and stable complexes formed between these enzymes and antimalarial drugs (chloroquine, artemisinin, primaquine, pyrimethamine, sulfadoxine and pentamidine) were modelled using AutoDock vina. Our data indicate that pf-TERT and pf-DHPS form stable complexes with the antimalarial ligands with affinity ranging from 𕒸.0 to 𕒺.9 kcal/mol. The affinity with crystal structures of DHFR receptors was higher ranging from 𕒺.0 to 󔼒.0 kcal/mol. The affinity to DHFR also decreases with the mutation a confirmation of the source of resistance. The highest affinity interaction for all the receptors modeled is observed with Artemisinin a benchma

关键词： Malaria Binding Energy Dihydrofolate Reductase Dihydropteroate

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