HYDROGEN BONDING

Contents

• Introduction

• Hydrogen bonding

• Molecular size

• Rotatable bonds

• Bulk physical properties

• Lipinski Rule of Five

• The Drug Design Conundrum

Intended learning outcomes

At the end of this lecture, student will be able to:

• Explain the importance of hydrogen bonding of drug molecules on biological action

Hydrogen bonding

• To form Intermolecular hydrogen bonds a hydrogen bond between a donor and acceptor group, both the donor and the acceptor must first break their hydrogen bonds to surrounding water molecules

• The position of this equilibrium depends on the relative energies of the species on either side, and not just the energy of the donor- acceptor complex

• Intramolecular hydrogen bonds are more readily formed in water - they are entropically more favourable.

Hydrogen bonding and bioavailability

Remember! Most oral drugs are absorbed through the gut wall by transcellular absorption.

• De-solvation and formation of a neutral molecule is unfavourable if the compound forms many hydrogen or ionic bonds with water.

• So, as a good rule of thumb, you don’t want too many hydrogen bond donors or acceptors, otherwise the drug won’t get from the gut into the blood.

• There are some exceptions to this – sugars, for example, but these have special transport mechanisms.

Molecular size

Molecular size is one of the most important factors affecting biological activity, but it’s also one of the most difficult to measure.

There are various ways of investigating the molecular size, including measurement of:

• Molecular weight (most important)

• Electron density

• Polar surface area

• Van der Waals surface

• Molar refractivity

Molecular weight

Number of rotatable bonds

A rotatable bond is defined as any single non-ring bond, attached to a non-terminal, non-hydrogen atom. Amide C-N bonds are not counted because of their high barrier to rotation.

The number of rotatable bonds influences, in particular, bioavailability and binding potency.

Remember δG = δH – TδS ! A molecule will have to adopt a fixed conformation to bind, and to pass through a membrane. This involves a loss in entropy, so if the molecule is more rigid to start with, less entropy is lost. But beware!

Bulk physical properties

When a compound is nearing nomination for entry to clinical trials, we need to look at:

• Solubility, including in human intestinal fluid

• Hygroscopicity, i.e. how readily a compound absorbs water from the atmosphere

• Crystalline forms – may have different properties

• Chemical stability (not a physical property! Look at stability to pH, temperature, water, air etc)

How can these be altered?

• Different counter ion or salt

• Different method of crystallisation

This seems like a lot to remember!

There are various guidelines to help, the most well-known of which is the Lipinski Rule of Five

• Molecular weight < 500

• logP < 5

• < 5 H-bond donors

• < 10 H-bond acceptors

An additional rule was proposed by Veber

• < 10 rotatable bonds

Otherwise absorption and bioavailability are likely to be poor. This is for oral drugs only.

The Drug Design Conundrum

The conundrum is that while pharmacokinetic properties improve by modulating bulk properties, potency also depends on these – particularly lipophilicity. There are then three approaches that could be adopted.