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Discovery of Traditional Chinese Medicine Derived Compounds as Wild Type and Mutant Plasmodium falciparum Dihydrofolate Reductase Inhibitors: Induced Fit Docking and ADME Studies

Author(s):

Opeyemi Iwaloye*, Olusola Olalekan Elekofehinti, Babatomiwa Kikiowo, Toyin Mary Fadipe, Moses Orimoloye Akinjiyan, Esther Opeyemi Ariyo, Olabisi Olapade Aiyeku and Nicholas Adeyemi Adewumi   Pages 1 - 16 ( 16 )

Abstract:


Background: In a bid to come up with effective compounds as inhibitors in antimalarial treatment, we built a library containing about 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Data-base@Taiwan. The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolate reductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to coffer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition.

Results: We utilized virtual throughput screening and glide XP docking to screen the compounds, and 8 compounds were found to have promising docking score with both the wild type and mutant pfDHFR. They were further subjected to induced fit docking (IFD) to affirm their inhibitory potency. The ADME properties and biological activity spectrum of the com-pounds were also considered. Inspection of the inhibition profile of the compounds demonstrated that a number of the com-pounds form intermolecular interaction with ASP54, ILE14, LEU164, SER108/ASN108, ARG122 and ASP58. Majority of the compounds are considered to be drug candidates due to their antiprotozoal activities and accordance with Lipinski’s rule of five (ROF).

Conclusion: The outcome of the present study should further be investigated to attest the efficacy of these compounds as better drug candidates than the antifolates.

Keywords:

Traditional Chinese medicine (TCM), Antifolates, Lipinski’s rule of five (ROF), Antiprotozoal activities, ADME properties, biological activity spectrum

Affiliation:

Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Department of Biochemistry, Adekunle Ajasin University, Akungba Akoko, Ondo State, Department of Bioscience, International Institute of Agriculture, Ibadan, Oyo State, Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State, Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, Ondo State



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