Dataset Information

Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase).

ABSTRACT: Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc. Proteins of Ras family undergo farnesylation by FTase while Rho family goes through geranylgeranylation by GGTase1. There is only an infinitesimal difference in signal recognition between FTase and GGTase1. FTase inhibitors mostly end up selecting the cells with mutated Ras proteins that have acquired affinity towards GGTase1 in cancer microcosms. Therefore, it is of interest to identify GGTase1 and FTase dual inhibitors using the docking tool AutoDock Vina. Docking data show that curcumin (from turmeric) has higher binding affinity to GGTase1 than that of established peptidomimetic GGTase1 inhibitors (GGTI) such as GGTI-297, GGTI-298, CHEMBL525185. Curcumin also interacts with FTase with binding energy comparable to co-crystalized compound 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(1-methyl-1h-imidizol-5-yl)-ethyl]-benzonitrile (BNE). The docked complex was further simulated for 10 ns using molecular dynamics simulation for stability. Thus, the molecular basis for curcumin binding to GGTase1 and FTase is reported.

SUBMITTER: Subramani PA

PROVIDER: S-EPMC4464541 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase).

Subramani Parasuraman Aiya PA Narala Venkata Ramireddy VR Michael R Dinakaran RD Lomada Dakshayani D Reddy Madhava C MC

Bioinformation 20150528 5

Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc. Proteins of Ras family undergo farnesylation by FTase while Rho family goes through geranylgeranylation by GGTase1. There is only an infinitesimal difference in signal recognition between FTase and GGTase1. FTase inhibitors mostly end up selecting the cells with mutated Ras proteins that have acquired affinity towards GGTase1 in cancer microcosms. Therefore, ...[more]

PMID: 26124569

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Project description:Curcumin is an extensively studied natural compound due to its extensive biological applications. However, there are some drawbacks linked to this compound such as poor absorption, low water-solubility, quick systemic elimination, fast metabolism, poor pharmacokinetics, low bioavailability, low penetration targeting efficacy and low stability. To overcome these drawbacks, curcumin is encapsulated in nano-carriers. In the current studies, we synthesized nanoparticles of curcumin without using nanocarriers by different methods such as nano-suspension (Cur-NSM), sonication (Cur-SM) and anti-solvent precipitation (Cur-ASP) to enhance the solubility of curcumin in water. The prepared nanoparticles were characterized by FTIR, SEM and XRD analysis. These curcumin nanoparticles were screened for their solubilities in water, DPPH scavenging, amylase, α-glucosidase and β-glucosidase enzymatic activities. The particle size of nano-curcumin was found to be in the 47.4-98.7 nm range. The reduction in particle size of curcumin dramatically increases its solubility in water to 79.2 μg mL-1, whereas the solubility of curcumin is just 0.98 μg mL-1. Cur-ASP showed the highest free radical scavenging potential (48.84 ± 0.98%) which was comparable with standard BHT (50.48 ± 1.11%) at 75.0 μg mL-1. As well, Cur-ASP showed the highest inhibition of α-amylase (68.67 ± 1.02%), α-glucosidase (58.30 ± 0.52%), and β-glucosidase (64.80 ± 0.43%) at 100 μg mL-1 which is comparable with standard drug acarbose. The greater surface area of nanoparticles exposes the various groups of curcumin for blocking the binding sites of enzymes. This strategy may be helpful in designing curcumin as a potent therapeutic agent against diabetes mellitus. Further, the molecular interactions of curcumin with α-amylase, α-glucosidase, β-glucosidase, and polyphenol oxidase were assessed by analyzing the plausible binding modes of curcumin in the binding pocket of each receptor. The best binding mode of curcumin was used to make complexes with the target proteins and their stability was confirmed by 50 ns MD simulation.

Project description:BackgroundIsoprenoids are the most diverse and abundant group of natural products. In Plasmodium falciparum, isoprenoid synthesis proceeds through the methyl erythritol diphosphate pathway and the products are further metabolized by farnesyl diphosphate synthase (FPPS), turning this enzyme into a key branch point of the isoprenoid synthesis. Changes in FPPS activity could alter the flux of isoprenoid compounds downstream of FPPS and, hence, play a central role in the regulation of a number of essential functions in Plasmodium parasites.MethodsThe isolation and cloning of gene PF3D7_18400 was done by amplification from cDNA from mixed stage parasites of P. falciparum. After sequencing, the fragment was subcloned in pGEX2T for recombinant protein expression. To verify if the PF3D7_1128400 gene encodes a functional rPfFPPS protein, its catalytic activity was assessed using the substrate [4-14C] isopentenyl diphosphate and three different allylic substrates: dimethylallyl diphosphate, geranyl diphosphate or farnesyl diphosphate. The reaction products were identified by thin layer chromatography and reverse phase high-performance liquid chromatography. To confirm the product spectrum formed of rPfFPPS, isoprenic compounds were also identified by mass spectrometry. Apparent kinetic constants KM and Vmax for each substrate were determined by Michaelis-Menten; also, inhibition assays were performed using risedronate.ResultsThe expressed protein of P. falciparum FPPS (rPfFPPS) catalyzes the synthesis of farnesyl diphosphate, as well as geranylgeranyl diphosphate, being therefore a bifunctional FPPS/geranylgeranyl diphosphate synthase (GGPPS) enzyme. The apparent KM values for the substrates dimethylallyl diphosphate, geranyl diphosphate and farnesyl diphosphate were, respectively, 68?±?5 ?M, 7.8?±?1.3 ?M and 2.06?±?0.4 ?M. The protein is expressed constitutively in all intra-erythrocytic stages of P. falciparum, demonstrated by using transgenic parasites with a haemagglutinin-tagged version of FPPS. Also, the present data demonstrate that the recombinant protein is inhibited by risedronate.ConclusionsThe rPfFPPS is a bifunctional FPPS/GGPPS enzyme and the structure of products FOH and GGOH were confirmed mass spectrometry. Plasmodial FPPS represents a potential target for the rational design of chemotherapeutic agents to treat malaria.

Dataset Information

Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase).

Publications

Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase).

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