title: Structure Based Docking and Molecular Dynamic Studies of Plasmodial Cysteine Proteases against a South African Natural Compound and its Analogs.
abstract: Identification of potential drug targets as well as development of novel antimalarial chemotherapies with unique mode of actions due to drug resistance by Plasmodium parasites are inevitable. Falcipains (falcipain-2 and falcipain-3) of Plasmodium falciparum, which catalyse the haemoglobin degradation process, are validated drug targets. Previous attempts to develop peptide based drugs against these enzymes have been futile due to the poor pharmacological profiles and susceptibility to degradation by host enzymes. This study aimed to identify potential non-peptide inhibitors against falcipains and their homologs from other Plasmodium species. Structure based virtual docking approach was used to screen a small non-peptidic library of natural compounds from South Africa against 11 proteins. A potential hit, 5α-Pregna-1,20-dien-3-one (5PGA), with inhibitory activity against plasmodial proteases and selectivity on human cathepsins was identified. A 3D similarity search on the ZINC database using 5PGA identified five potential hits based on their docking energies. The key interacting residues of proteins with compounds were identified via molecular dynamics and free binding energy calculations. Overall, this study provides a basis for further chemical design for more effective derivatives of these compounds. Interestingly, as these compounds have cholesterol-like nuclei, they and their derivatives might be well tolerated in humans.
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
authors.forename: Thommas M
authors.initials: TM
authors.lastname: Musyoka
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.|Department of Genetics, Forestry and Agricultural Biotechnology Institute (FABI), Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria, South Africa.
authors.forename: Aquillah M
authors.initials: AM
authors.lastname: Kanzi
authors.affiliation: Department of Chemistry, Rhodes University, Grahamstown, South Africa.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Lobb
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Tastan Bishop
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry; D002403:Cathepsins / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D030562:Databases, Protein; D004351:Drug Resistance; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000201:enzymology; D011245:Pregnadienes / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry; D013019:South Africa; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D001688:Biological Products; D006454:Hemoglobins; D011245:Pregnadienes; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3