scholarly journals Enhanced Solubility and Anticancer Potential of Mansonone G By β-Cyclodextrin-Based Host-Guest Complexation: A Computational and Experimental Study

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 545 ◽  
Author(s):  
Mahalapbutr ◽  
Wonganan ◽  
Charoenwongpaiboon ◽  
Prousoontorn ◽  
Chavasiri ◽  
...  
Keyword(s):  
Water Solubility ◽  
Binding Free Energy ◽  
Inclusion Complexation ◽  
Host Molecule ◽  
Inclusion Complex Formation ◽  
Practical Applications ◽  
Enhanced Solubility ◽  
Poorly Soluble ◽  
Dynamics Simulations ◽  
A549 Lung

Mansonone G (MG), a plant-derived compound isolated from the heartwood of Mansonia gagei, possesses a potent antitumor effect on several kinds of malignancy. However, its poor solubility limits the use for practical applications. Beta-cyclodextrin (βCD), a cyclic oligosaccharide composed of seven (1→4)-linked α-D-glucopyranose units, is capable of encapsulating a variety of poorly soluble compounds into its hydrophobic interior. In this work, we aimed to enhance the water solubility and the anticancer activity of MG by complexation with βCD and its derivatives (2,6-di-O-methyl-βCD (DMβCD) and hydroxypropyl-βCD). The 90-ns molecular dynamics simulations and MM/GBSA-based binding free energy results suggested that DMβCD was the most preferential host molecule for MG inclusion complexation. The inclusion complex formation between MG and βCD(s) was confirmed by DSC and SEM techniques. Notably, the MG/βCDs inclusion complexes exerted significantly higher cytotoxic effect (2–7 fold) on A549 lung cancer cells than the uncomplexed MG.

scholarly journals Quality Enhancement by Inclusion Complex Formation of Simvastatin Tablets

2013 ◽  
Vol 59 (4) ◽  
pp. 223-225
Author(s):  
Rédai Emőke ◽  
Sipos Emese ◽  
Pocsai Zs ◽  
Tőkés B ◽  
Székely P
Keyword(s):  
Inclusion Complex ◽  
Inclusion Complexation ◽  
Molar Ratio ◽  
Physical Parameters ◽  
Quality Enhancement ◽  
Direct Compression ◽  
Dissolution Profile ◽  
Host Molecule ◽  
Inclusion Complex Formation ◽  
Dissolution Properties

Abstract Introduction: Simvastatin is an inhibitor of hydroxy-methyl-glutaryl-coenzyme A reductase, used in the treatment of hypercholesterolemia. To enhance its bioavailability by inclusion complexation, as host molecule randommethyl-β-cyclodextrin had been used. After evaluating the complexes we chose the kneading product in 1:2 molar ratio for incorporation of 10 mg simvastatin tablets. Materials and methods: We prepared homogenous mixtures of the inclusion complex and some excipients. The tablets were prepared by direct compression. The tablets were evaluated in regard to: weight uniformity, thickness, diameter, hardness, friability, disintegration and dissolution profile. Results: Weights are in the range of 196-208 mg, diameter 6.83-6.86 mm, height 3.86-4.01 mm, hardness 78.3-113.1 N, friability 0.75- 1.19 %, disintegration above 15 minutes. The dissolved amounts of simvastatin from the tablets are higher compared to the dissolution of pure simvastatin, but lower than the dissolution of the complex itself. Excipients, like disintegrants and lubricants greatly influence the dissolution properties of the tablets. Conclusions: According to our results, tablets containing inclusion complex of simvastatin exhibit better solubility, according to the dissolved amount of simvastatin, than pure drug alone. Proper physical parameters of the tablets are obtained by application of 5 % Primellose

scholarly journals Inclusion complexes of pesticides in aqueous solutions of methylated-β-cyclodextrin

2013 ◽  
Vol 67 (2) ◽  
pp. 231-237 ◽  
Author(s):  
Goran Petrovic ◽  
Gordana Stojanovic ◽  
Olga Jovanovic ◽  
Aleksandra Djordjevic ◽  
Ivan Palic ◽  
...  
Keyword(s):  
Aqueous Solution ◽  
Water Solubility ◽  
Inclusion Complexation ◽  
Solubility In Water ◽  
Other Substances ◽  
Poorly Soluble ◽  
Enthalpy And Entropy ◽  
Methylated Cyclodextrin ◽  
Organic Pesticides ◽  
Hplc Data

Disadvantage of some organic pesticides is their low water solubility. Among other substances, cyclodextrins and modified cyclodextrins were considered as agents for improving pesticides water solubility. The solubility of poorly soluble pesticides, dimethoate, simazine, linuron and thiram, was determined in aqueous solution of methylated-?-cyclodextrin (mbCD) by ultraviolet spectrophotometry. Methylated-?-cyclodextrin was obtained by the modified Hawort method and characterized by 1H NMR and HPLC data. The average degree of substitution was 13.8. Methylation was done either on C-2, C-3, and C-6 atoms of glucopyranose unit therefore obtained product can be assort as randomly m?CD. Solubility of the studied pesticides in aqueous solution of m?CD increases in relation to their solubility in water for dimethoate 506, for simazine167, for thiram 44, and for linuron 20 times. Reactions of dimethoate and simazine with m?CD were entropy-driven while the inclusion complexation of m?CD with the linuron and thiram were driven by both, enthalpy and entropy, as determined by calorimetric measurements. The observed solubility increment of the investigated pesticides in aqueous solution of m?CD, suggests that it can be efficiently used in pesticide solutions formulations and increase their bioavailability, and biodegradability.

scholarly journals Distinct Binding Dynamics, Sites and Interactions of Fullerene and Fullerenols with Amyloid-β Peptides Revealed by Molecular Dynamics Simulations

2019 ◽  
Vol 20 (8) ◽  
pp. 2048 ◽  
Author(s):  
Zhiwei Liu ◽  
Yu Zou ◽  
Qingwen Zhang ◽  
Peijie Chen ◽  
Yu Liu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Water Solubility ◽  
Binding Free Energy ◽  
Critical Role ◽  
Amyloid Β ◽  
Fullerene C60 ◽  
Water Soluble ◽  
Hydroxyl Groups ◽  
Dynamics Simulations

The pathology Alzheimer’s disease (AD) is associated with the self-assembly of amyloid-β (Aβ) peptides into β-sheet enriched fibrillar aggregates. A promising treatment strategy is focused on the inhibition of amyloid fibrillization of Aβ peptide. Fullerene C60 is proved to effectively inhibit Aβ fibrillation while the poor water-solubility restricts its use as a biomedicine agent. In this work, we examined the interaction of fullerene C60 and water-soluble fullerenol C60(OH)6/C60(OH)12 (C60 carrying 6/12 hydroxyl groups) with preformed Aβ40/42 protofibrils by multiple molecular dynamics simulations. We found that when binding to the Aβ42 protofibril, C60, C60(OH)6 and C60(OH)12 exhibit distinct binding dynamics, binding sites and peptide interaction. The increased number of hydroxyl groups C60 carries leads to slower binding dynamics and weaker binding strength. Binding free energy analysis demonstrates that the C60/C60(OH)6 molecule primarily binds to the C-terminal residues 31–41, whereas C60(OH)12 favors to bind to N-terminal residues 4–14. The hydrophobic interaction plays a critical role in the interplay between Aβ and all the three nanoparticles, and the π-stacking interaction gets weakened as C60 carries more hydroxyls. In addition, the C60(OH)6 molecule has high affinity to form hydrogen bonds with protein backbones. The binding behaviors of C60/C60(OH)6/C60(OH)12 to the Aβ40 protofibril resemble with those to Aβ42. Our work provides a detailed picture of fullerene/fullerenols binding to Aβ protofibril, and is helpful to understand the underlying inhibitory mechanism.

Crystal Engineering for Enhanced Solubility and Bioavailability of Poorly Soluble Drugs

2018 ◽  
Vol 24 (21) ◽  
pp. 2473-2496 ◽  
Author(s):  
Jaleh Varshosaz ◽  
Erfaneh Ghassami ◽  
Saeedeh Ahmadipour
Keyword(s):  
Crystal Engineering ◽  
Water Solubility ◽  
Solid Dispersions ◽  
Pharmaceutical Sciences ◽  
Pharmaceutical Ingredients ◽  
Drug Molecules ◽  
Enhanced Solubility ◽  
Wide Range ◽  
Poorly Soluble ◽  
Low Solubility

Background: Crystal engineering is dealing with the creation of new structures and new properties in drug molecules through inter-molecular interactions. Researchers of pharmaceutical sciences have used this knowledge to alter the structure of crystalline medications in order to remedy the problems of more than 40% of the new designed drugs which suffer from low solubility and consequently, low bioavailability which have limited their clinical application. Methods: This review covers a broad spectrum of aspects of the application of crystal engineering in pharmaceutics and includes a comprehensive wide range of different techniques used in crystal engineering of active pharmaceutical ingredients (API) to compensate the low water solubility and bioavailability of drugs related specially to class II of biopharmaceutical classification system (BCS). Results: These techniques include; crystalline habit modification, polymorphism, solvates and hydrates, cocrystals, surface modification, crystallization, spherical agglomeration, liquisolid crystals and solid dispersions which are introduced and discussed in this review article. Conclusion: Each of these techniques has advantages and limitations which are emphasized on them.

Molecular dynamics simulations and binding free energy analysis of DNA minor groove complexes of curcumin

2011 ◽  
Vol 17 (11) ◽  
pp. 2805-2816 ◽  
Author(s):  
Mathew Varghese Koonammackal ◽  
Unnikrishnan Viswambharan Nair Nellipparambil ◽  
Chellappanpillai Sudarsanakumar
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Energy Analysis ◽  
Binding Free Energy ◽  
Minor Groove ◽  
Dna Minor Groove ◽  
Dynamics Simulations ◽  
Free Energy Analysis

scholarly journals Molecular Dynamic Simulation Analysis on the Inclusion Complexation of Plumbagin with β-Cyclodextrin Derivatives in Aqueous Solution

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6784
Author(s):  
Kulpavee Jitapunkul ◽  
Pisanu Toochinda ◽  
Luckhana Lawtrakul
Keyword(s):  
Aqueous Solution ◽  
Slow Release ◽  
Storage Temperature ◽  
Simulation Analysis ◽  
Inclusion Complexation ◽  
Storage Life ◽  
Release Mechanism ◽  
Guest Binding ◽  
Binding Cavity ◽  
Dynamics Simulations

Stable encapsulation of medically active compounds can lead to longer storage life and facilitate the slow-release mechanism. In this work, the dynamic and molecular interactions between plumbagin molecule with β-cyclodextrin (BCD) and its two derivatives, which are dimethyl-β-cyclodextrin (MBCD), and 2-O-monohydroxypropyl-β-cyclodextrin (HPBCD) were investigated. Molecular dynamics simulations (MD) with GLYCAM-06 and AMBER force fields were used to simulate the inclusion complex systems under storage temperature (4 °C) in an aqueous solution. The simulation results suggested that HPBCD is the best encapsulation agent to produce stable host–guest binding with plumbagin. Moreover, the observation of the plumbagin dynamic inside the binding cavity revealed that it tends to orient the methyl group toward the wider rim of HPBCD. Therefore, HPBCD is a decent candidate for the preservation of plumbagin with a promising longer storage life and presents the opportunity to facilitate the slow-release mechanism.

scholarly journals Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

2020 ◽  
Vol 26 (42) ◽  
pp. 7598-7622 ◽  
Author(s):  
Xiao Hu ◽  
Irene Maffucci ◽  
Alessandro Contini
Keyword(s):  
Drug Discovery ◽  
Binding Free Energy ◽  
Docking Studies ◽  
Free Energy Calculations ◽  
Binding Energies ◽  
New Drugs ◽  
Water Molecules ◽  
Open Questions ◽  
Dynamics Simulations ◽  
Computational Drug Discovery

Background: The inclusion of direct effects mediated by water during the ligandreceptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions. Objective: In this review, we will discuss some of the most recent methods that can be used in computational drug discovery and drug development when the effect of a single water, or of a small network of interacting waters, needs to be explicitly considered. Results: Here, we analyse the software to aid the selection, or to predict the position, of water molecules that are going to be explicitly considered in later docking studies. We also present software and protocols able to efficiently treat flexible water molecules during docking, including examples of applications. Finally, we discuss methods based on molecular dynamics simulations that can be used to integrate docking studies or to reliably and efficiently compute binding energies of ligands in presence of interfacial or bridging water molecules. Conclusions: Software applications aiding the design of new drugs that exploit water molecules, either as displaceable residues or as bridges to the receptor, are constantly being developed. Although further validation is needed, workflows that explicitly consider water will probably become a standard for computational drug discovery soon.

scholarly journals Computational investigation on the role of C-Terminal of human albumin on the dimerization of Aβ1-42 peptide

2020 ◽  
Vol 10 (1) ◽  
pp. 4944-4955 ◽  
Keyword(s):  
Computational Study ◽  
Binding Free Energy ◽  
Conformational Dynamics ◽  
Human Albumin ◽  
Potential Of Mean Force ◽  
Amber Force Field ◽  
Aβ Aggregation ◽  
The Difference ◽  
Dynamics Simulations

Alzheimer’s disease (AD) is characterized by the presence of Amyloid-beta (Aβ) peptide, which has the propensity to fold into β-sheets under stress forming aggregated amyloid plaques. Nowadays many studies have focused on the development of novel, specific therapeutic strategies to slow down Aβ aggregation or control preformed aggregates. Albumin, the most abundant protein in the cerebrospinal fluid, was reported to bind Aβ impeding its aggregation. Recently, it has been reported that C-terminal (CTerm) of Human Albumin binds with Aβ1-42, impairs Aβ aggregation and promotes disassembly of Aβ aggregates protecting neurons. In this computational study, we have investigated the effect of CTerm on the conformational dynamics and the aggregation propensity of Aβ1-42 peptide. We have performed molecular dynamics simulations on the Aβ1-42-Aβ1-42 homodimer and Aβ1-42-CTerm of albumin heterodimer using the AMBER force field ff99SBildn. From the Potential of mean force (PMF) study and Binding free energy (BFE) analysis, we observed the association of Aβ1-42 peptide monomer with itself in the form of homodimer to be stronger than its association with the CTerm in the heterodimer complex. The difference in the number of residues in the Aβ1-42 peptide monomer (42 AAs) and CTerm (35 AAs) may be probable reason for the difference in association between the monomeric units in corresponding homodimer and heterodimer complexes. But even then CTerm shows a significant effect on the dimerization of Aβ1-42 peptide. Our findings therefore suggest that CTerm can be used for the disassembly of Aβ1-42 peptide monomer.

scholarly journals The Role of Cyclodextrins in the Design and Development of Triterpene-Based Therapeutic Agents

2022 ◽  
Vol 23 (2) ◽  
pp. 736
Author(s):  
Alexandra Prodea ◽  
Alexandra Mioc ◽  
Christian Banciu ◽  
Cristina Trandafirescu ◽  
Andreea Milan ◽  
...  
Keyword(s):  
Water Solubility ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Biological Behavior ◽  
Therapeutic Effects ◽  
Practical Applications ◽  
Starch Derivatives ◽  
Solubility Enhancers ◽  
Low Solubility

Triterpenic compounds stand as a widely investigated class of natural compounds due to their remarkable therapeutic potential. However, their use is currently being hampered by their low solubility and, subsequently, bioavailability. In order to overcome this drawback and increase the therapeutic use of triterpenes, cyclodextrins have been introduced as water solubility enhancers; cyclodextrins are starch derivatives that possess hydrophobic internal cavities that can incorporate lipophilic molecules and exterior surfaces that can be subjected to various derivatizations in order to improve their biological behavior. This review aims to summarize the most recent achievements in terms of triterpene:cyclodextrin inclusion complexes and bioconjugates, emphasizing their practical applications including the development of new isolation and bioproduction protocols, the elucidation of their underlying mechanism of action, the optimization of triterpenes’ therapeutic effects and the development of new topical formulations.

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