CCP5 - Complexation of Cyclodextrins

Project Investigator

C W Yong

Scientific/ Technical Objectives

To understand the behaviour of CD derivatives in water and their small molecule encapsulation behaviour.

Cyclodextrins (CDs) are a group of oligosaccharides which consist of glucose units connected together to form a ring structure. They are readily available from enzymatic hydrolysis of starch. The naturally occurring CDs usually consist of six member (?), seven member (?) and eight member (?) glucose units and have near-perfect circular shape, adopting approximate truncated cylindrical cone (Fig 1).

Side and top views of a minimised b-CD molecule showing solvent accessibility surface in mesh

The arrangements of these units are such that the cavities of the CD molecules are highly hydrophobic whereas the rims are highly hydrophilic. This unique structure allows the CD molecules to dissolve in water while retaining a capability of encapsulating hydrophobic molecules. For this reason, CD-based technologies have been widely exploited in the pharmaceutical, food science and cosmetic industries. In the pharmaceutical application, the encapsulation capabilities of CDs are used to increase the solubility, stability and bioavailability of drugs and to prevent undesirable drug-drug interactions.

We at the Daresbury Laboratory (DL), in collaboration with the AstraZeneca (AZ) production team at Macclesfield, have carried out systematic investigations of these complex molecules to gain understanding of the atomistic processes of the molecular encapsulation behaviour. The project is a synergistic combination of computational and experimental approaches which ensures that the challenging research work is carried out efficiently. This combines the molecular simulation expertise at DL, which makes use of the NW-Grid parallelized computational resources, and the experimental knowledge of the AZ group.

It is our aim to use molecular dynamics techniques to investigate systematically a selected range of 2-hydroxypropyl substituted CDs (2-HPBCD) in order to identify the important characteristic features of molecular encapsulation for selected drug molecules and determine the corresponding solubility. This modified CD is considered to be the most desirable due to its high solubility in water and low toxicity data in drug formulations.

The two diagrams above show that how different degree of substitution of side chains on the ?-CDs can influence the way the guest molecule (highlighted in green) can be complexed. In this case, the example guest molecule is 9-fluorenone, a polycyclic aromatic hydrocarbon that is used in manufacturing antimalaria drugs and other pharmaceuticals.

These results show that the interactions of the guest molecule within the hosts' cavities are strongly influenced by the locations of the 2-hydroxypropyl derivatives. Such information is valuable in predicting the mechanisms of molecular encapsulation of new guest molecules and their corresponding solubility and complexation behaviour in water.

Currently exploring using the eMinerals infrastructure to launch multiple simulations.

Role of NW-GRID

Provide computational resources for molecular simulations.

Applications Software

DL_POLY_2, DL_POLY_3

Grid Software

Globus - eMinerals Infrastructure

Progress to date

Ongoing.

Publications

In preparation, to be submitted to Pharm. Res. journal