Docking and in silico ADMET studies of noraristeromycin, curcumin and its derivatives with Plasmodium falciparum SAH hydrolase: A molecular drug target against malaria

Abstract

The Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (pfSAHH) enzyme has been considered as a potential chemotherapeutic target against malaria due to the amino acid differences found on binding sites of pfSAHH related to human SAHH. It has been reported that noraristeromycin and some curcumin derivatives have potential binding with the largest cavity of pfSAHH, which is also related to the binding with Nicotinamide-Adenine-Dinucleotide (NAD) and Adenosine (ADN). Our present work focuses on docking and ADMET studies to select potential inhibitors of pfSAHH. The binding of the selected inhibitor of the PfSAHH active site was analyzed using Molegro Virtual Docker. In this study, curcumin and its derivatives have been found to have higher binding affinity with pfSAHH than noraristeromycin. Seven amino acid residues Leu53, His54, Thr56, Lys230, Gly397, His398 and Phe407 of pfSAHH involved in binding with curcumin, are the same as those for noraristeromycin, which reveals that curcumin and noraristeromycin bind in the same region of pfSAHH. Curcumin has shown a strong interaction with hydrophobic amino acid residues of pfSAHH. Molecular Docking and ADMET predictions suggest that curcumin can be a potent inhibitor of pfSAHH with ability to modulate the target in comparatively smaller dose. Therefore, curcumin is likely to become a good lead molecule for the development of effective drug against malaria.

Developing imidazole analogues as potential inhibitor forLeishmania donovanitrypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach

“…To develop an effective oral drug, the MRTD value should be greater than 3.16, which confirm that the selected compound is "inactive" with fewer side effect and vice versa (Matthews, Kruhlak, Benz, & Contrera, 2004;Singh et al, 2013). The present study show that nineteen compounds including NI2 (clomipramine) showed MRTD value greater than 3.16 with few other side effects.…”

“…It uses ADMET modeler module to build predictive models for new properties from user's data. The mathematical model in the program uses molecular descriptor value to generate estimate for each ADMET properties (Fraczkiewicz et al, 2015;Singh, Gupta, Singh, Singh, & Misra, 2013). Schrödinger QikProp is rapid, accurate and convenient program, used to predict pharmaceutically applicable ADME (Absorption, Distribution, Metabolism and Excretion) properties of drug molecule.…”

“…It can be run from MAESTRO GUI or directly through command line program. It is used to generate a number of output properties like hydrogen bond, solvent accessible surface (SASA), conjugated amine group, polarizability after drug administration (Singh et al, 2013).…”

Molecular drug targets and therapies for Alzheimer’s disease

“…It is important to design analogues of these inhibitors with high specificity to their target, and their QSAR and ADMET properties must be predicted before synthesis and clinical trial [136]. Cu in the aged hippocampus [143].…”

Structural insight into binding mode of inhibitor with SAHH of Plasmodium and human: interaction of curcumin with anti-malarial drug targets

“…Curcumin binds with Leu53, His54, Thr56, Lys230, Gly397, His398, and Phe407 residues of PfSAHH, and these residues also observed in interaction with noraristeromycin. Curcumin and noraristeromycin utilize the same site of PfSAHH for binding [11,12]. P. falciparum is responsible for millions of deaths each year.…”