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Identification of potential drug target in malarial disease using molecular docking analysis.

ABSTRACT: Malaria caused by genus Plasmodium, is a parasite which is the main health issue for humans and about half of the population were suffered. An every year, approximately 1.2-2.7 million people died due to malaria globally. Therefore to prevent the spreading of malaria from the glob novel active drugs with specific activities are necessary. The present study aimed to identify novel drug molecule together with the bioinformatic tools for the development of active malarial drugs. As the search for latest anti malarial compound was developed, this work determined six active blends from various drug databases which possess drug-like characteristics and presents a significant anti malarial actions in in-silico level. Compound ID 300238, 889, 76569, 87324, 45678, and Z185397112are a few of the ligands were got from the Toss lab, Maybridge, Cambridge, Life chem, Bitter, and Examine drug databases and docked against hexokinase 1 protein (PDB: 1CZA) with high throughput practical screening (HTVS) using Glide v6.6. Amid the 6 compounds, compound no: 300238 from Toss lab has the greatest docking score of -9.889 kcal/mol targeting 1CZA protein. The active sites of Hexokinase I of protein were determine by using superimposition of the destination and template structure showed similar structural folds and active sites which were decidedly conserved. The quality of hexokinase I protein was considered to be sterically stable where the protein was prepared by utilizing the software protein preparation execute in the Schrodinger suite. Prepared proteins were evaluated using SAVES and the studies of molecular dynamics of the hexokinase, and the GROMACS were performed for protein-ligand complex. The low HOMO-LUMO energy gaps of the compound verified the greater stability of the molecule. Here, the tested drug candidates have good absorption, distribution, metabolism, and excretion (ADME) properties which were established by using QikProp, version 3.4 of Schrodinger.

SUBMITTER: Joseph Sahayarayan J

PROVIDER: S-EPMC7715035 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Identification of potential drug target in malarial disease using molecular docking analysis.

Joseph Sahayarayan Jesudass J Soundar Rajan Kulanthaivel K Nachiappan Mutharasappan M Prabhu Dhamodharan D Guru Raj Rao Ravi R Jeyakanthan Jeyaraman J Hossam Mahmoud Ahmed A Mohammed Osama B OB Morgan Abubaker M A AMA

Saudi journal of biological sciences 20201016 12

Malaria caused by genus <i>Plasmodium, is</i> a parasite which is the main health issue for humans and about half of the population were suffered. An every year, approximately 1.2-2.7 million people died due to malaria globally. Therefore to prevent the spreading of malaria from the glob novel active drugs with specific activities are necessary. The present study aimed to identify novel drug molecule together with the bioinformatic tools for the development of active malarial drugs. As the searc ...[more]

PMID: 33304138

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Project description:BACKGROUND: Based on resistance of currently used anti-malarials, a new anti-malarial drug target against Plasmodium falciparum is urgently needed. Damaged DNA cannot be transcribed without prior DNA repair; therefore, uracil-DNA glycosylase, playing an important role in base excision repair, may act as a candidate for a new anti-malarial drug target. METHODS: Initially, the native PfUDG from parasite crude extract was partially purified using two columns, and the glycosylase activity was monitored. The existence of malarial UDG activity prompted the recombinant expression of PfUDG for further characterization. The PfUDG from chloroquine and pyrimethamine resistant P. falciparum strain K1 was amplified, cloned into the expression vector, and expressed in Escherichia coli. The recombinant PfUDG was analysed by SDS-PAGE and identified by LC-MS/MS. The three dimensional structure was modelled. Biochemical properties were characterized. Inhibitory effects of 12 uracil-derivatives on PfUDG activity were investigated. Inhibition of parasite growth was determined in vitro using SYBR Green I and compared with results from human cytotoxicity tests. RESULTS: The native PfUDG was partially purified with a specific activity of 1,811.7 units/mg (113.2 fold purification). After cloning of 966-bp PCR product, the 40-kDa hexa-histidine tagged PfUDG was expressed and identified. The amino acid sequence of PfUDG showed only 24.8% similarity compared with the human enzyme. The biochemical characteristics of PfUDGs were quite similar. They were inhibited by uracil glycosylase inhibitor protein as found in other organisms. Interestingly, recombinant PfUDG was inhibited by two uracil-derived compounds; 1-methoxyethyl-6-(p-n-octylanilino)uracil (IC50 of 16.75 ?M) and 6-(phenylhydrazino)uracil (IC50 of 77.5 ?M). Both compounds also inhibited parasite growth with IC50s of 15.6 and 12.8 ?M, respectively. Moreover, 1-methoxyethyl-6-(p-n-octylanilino)uracil was not toxic to HepG2 cells, with IC50 of > 160 ?M while 6-(phenylhydrazino)uracil exhibited cytoxicity, with IC50 of 27.5 ?M. CONCLUSIONS: The recombinant PfUDG was expressed, characterized and compared to partially purified native PfUDG. Their characteristics were not significantly different. PfUDG differs from human enzyme in its size and predicted amino acid sequence. Two uracil derivatives inhibited PfUDG and parasite growth; however, only one non-cytotoxic compound was found. Therefore, this selective compound can act as a lead compound for anti-malarial development in the future.

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Identification of potential drug target in malarial disease using molecular docking analysis.

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Identification of potential drug target in malarial disease using molecular docking analysis.

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