SAR & pharmacophore

Optimizing target interactions SAR & pharmacophore

MSc. HAYA SALEH EL-QADERI Faculty of pharmacy and medical

sciences Jadara university

Optimizing Target Interactions

• Once the lead compound has been discovered it can be used as the starting point for drug design.

• There are various aims in drug design: The drug should have a good selectivity for its target

The drug should have a good level of activity for its target

The drug should have minimum side effects

The drug should be easily synthesized

The drug should be chemically stable

The drug should have acceptable pharmacokinetics properties

The drug should be non-toxic

Optimizing Target Interactions

• There are two important aspects in drug design and drug strategies to improve : Pharmacodynamic properties: to optimize the interaction of the drug

with its target.

Pharmacokinetic properties: to improve the drug's ability to reach its target & to have acceptable lifetime.

• Pharmacodynamic and pharmacokinetics should have equal priority in influencing which strategies are used and which analogues are synthesized.

Structure-activity relationships

• Once the structure of lead compound is known, the medicinal chemist moves on to study its SAR.

• The aim is to discover which parts of the molecule are important to biological activity and which are not.

• X-ray crystallography and NMR can be used to study and identify important binding interactions between drug and active site.

• SAR is synthesizing compounds, where one particular functional group of the molecule is removed or altered.

• In this way it is possible to find out which groups are essential and which are not for biological effect.

Structure-activity relationships

• This involves testing all analogues for biological activity and comparing them with the original compound.

• If an analogue shows a significant lower activity, then the group that has been modified must be important.

• If the activity remain similar, then the group is not essential.

• It may be possible to modify some lead compounds directly to the required analogues and other analogues may be prepared by total synthesis.

Binding Role of Different Functional Groups

1. Functional groups such as alcohols, phenols, amines, esters, amides, carboxylic acids, ketones and aldehydes can interact with binding sites by means of hydrogen bonding.

Binding Role of Different Functional Groups

2. Functional groups such as amines, (ionized) quaternary ammonium salts and carboxylic acid can interact with binding sites by ionic bond.

Binding Role of Different Functional Groups

3. Functional groups such as alkenes and aromatic rings can interact with binding sites by means of Van der Waals interactions.

Binding Role of Different Functional Groups

• Alkyl substituent and the carbon skeleton of the lead compound can interact with hydrophobic regions of binding site by means of Van der Waals interactions.

• Interactions involving dipole moments or induced dipole moments may play a role in binding a lead compound to a binding site.

• Reactive functional groups such as alkyl halides may lead to irreversible covalent bonds being formed between a lead compound and its target. – E.g. alkylation of macromolecular target by alkyl halides

Structure-activity relationships

• The relevance of a functional group to binding can be determined by preparing analogues where the functional group is modified or removed in order to see whether activity is affected by such change.

• Some functional groups can be important to the activity of a lead compound for reasons other than target binding as they may play a role in the electronic or stereochemical properties of the compound or they may have an important pharmacokinetic role.

• Replacing a group in the lead compound with isostere (a group having the same valency) makes it easier to determine whether a particular property such as hydrogen bonding is important.

• In vitro testing procedures should be used to determine the SAR for target binding.

• The pharmacophore summarizes the important groups which are important in the binding of a lead compound to its target, as well as their relative positions in three dimensions (for a specific pharmacological activity).

Structure-activity relationships

• Aim- identify which are important for binding and/or activity.

• Method – Alter, remove or mask a functional group. – Test the analogue for activity

• Conclusions depends on the method of testing 1. In vitro: tests for binding interactions with target. 2. In vivo: tests for target binding interactions and/or

pharmacokinetics. – If in vitro activity drop, it implies group is important fir binding. – If in vivo activity unaffected, it implies group is not important.

MORPHINE

MORPHINE

• Morphine, C17H19NO3, is the most abundant of opium’s 24 alkaloids, accounting for 9-14% of opium-extract by mass.

• The drug morphine numbs pain, alters mood and induces sleep.

• Less popular and less mentioned effects include nausea, vomiting and decreased gastrointestinal motility.

• The 3D structure of morphine is fascinating.

• It consists of five rings, three of which are approximately in the same plane.

• The other two rings, including the nitrogen one, are each at right angles to the other trio.

Structure-activity relationships

• Codeine:

– ACTIVITY DROPS.

Structure-activity relationships

• Heroin

– Diamorphine

– narcotic

– Habit-forming

Structure-activity relationships

• 6-oxymorphine

– Activity unaffected

Structure-activity relationships

• Morphine

– Important groups for activity

Pharmacophore

• “a molecular framework that carries (phores) the essential features responsible for a drug’s (pharmacone) biological activity” Paul Erlich, early 1909.

• “a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecules activity” Peter Gund,1977

• “an enseble of steric and electronic features that is necessary to ensyre the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response” IUPAC definition 1998

Pharmacophore

• Common features:

HBD

HBA

+ve & -ve charged groups

Hydrophobic regions

Aromatic interaction

Pharmacophore

Define important groups involved in binding

Defines the relative positions of binding groups

Need to know the active conformation

Pharmacophore

• Structural 1D pharmacophore

– Number of atoms, type of atoms, Mwt… etc

• Structural 2D pharmacophore

– Defines minimum skeleton connecting important binding groups

Morphine

• Analgesic pharmacophore for opioids

Morphine

Pharmacophore

• 3D pharmacophore defines relative positions in space of important binding groups

• Example

Morphine

Morphine

Morphine

Generalized bonding type pharmacophore

• Defines relative positions in space of the binding interactions which are required for activity – HBD

– HBA

– Van der Waals interaction

– Ionic interaction

The Active Conformation

• The conformation adopted by a drug when it bind to its target.

• Identifying of the active conformation is required in order to identify the 3D pharmacophore.

• Conformational analysis - identifies possible conformations and their activities.

• Conformational analysis is difficult for simple flexible molecules with large numbers of conformations.

• Easier to compare activity of rigid analogues

Pharmacophore from target binding site