Structure-Activity Relationship (SAR)

• Structure-Activity Relationship (SAR) correlates a drug molecule's chemical structure with its biological activity.

Importance of SAR

• SAR optimizes initial "hits" from high throughput screening into drug "leads" and then into drug candidates.
• Secondary assays, including ADME and animal models, assists in preclinical data generation and candidate selection.
• SAR is essential for intellectual property, granting exclusive rights to a drug's structure and activity.
• A holistic comprehension of drug-target interactions is developed and SAR is used to optimize drug leads for clinical use.

Defining SAR

• SAR analyzes the relationship between a drug's chemical structure and its activity.
• SAR uses an iterative process to design new molecules based on initial hits, synthesizes them, assesses their biological activity, and analyzes the data.
• Chemistry, biology, math, statistics, modeling, and prediction skills are incorporated in SAR.

What SAR Provides

• SAR identifies specific molecular forces of interaction between a drug and its target.
• SAR identifies pharmacophores, which are chemical groups causing positive interactions.
• SAR determines non-essential molecular parts which may cause off-target binding, undesired effects or toxicity.
• Non-essential elements can be modified for optimization and to eliminate potential toxicity.

Pharmacophore

• Pharmacophores are chemical function groups on a molecule that interact with the target.
• Pharmacophore includes the group's structure, position, and stereochemistry.
• Medicinal chemists can determine the minimum structural features.
• If activity is lost upon truncation, the group's structure, location, and stereochemistry are specifically needed for activity, indicating it's part of the pharmacophore.
• If activity isn't lost upon truncation it isn't essential.

Core Scaffold

• Core scaffold is the portion of the molecule that holds the pharmacophore groups in the correct three-dimensional orientation for best interaction with the target.
• Core scaffold often includes rings to achieve a bioactive conformation within the target receptor binding pocket.
• Different molecules with varying core structures and pharmacophores groups can often bind the same target.

Privilege Scaffold

• Privilege scaffolds are common core scaffolds in drugs that bind different targets.
• The core achieves a certain shape, and the specific pharmacophores provide diverse activity.
• Further core and pharmacophore optimization can make drugs more specific for a desired target.

Specificity

• A specific ligand or drug binds to one receptor and evokes a response at that receptor.
• A non-specific ligand or drug binds a receptor but causes activity at some other receptor, indicating an indirect effect.

Using SAR

• SAR can increase specificity by focusing on a specific isomer or determining core necessity.
• Reducing the carbon chain in the second ring of the Aza-bicycle core causes a complete loss of activity.
• The carbon chain is important for activity and specificity.

Specificity vs. Selectivity

• Specificity: Drugs bind specifically to one receptor, causing activity changes.
• Selectivity: Drugs bind at one receptor significantly more strongly or have higher activity there, compared to others.

Quantifying Selectivity

• Drug fold selectivity measures the preference for a desirable target relative to other targets.
• Fold selectivity is calculated by dividing off-target activity by desired target activity.
• Lower EC50 results in higher fold selectivity.

Receptor Subtype Selectivity

• Drugs can be selective among the same receptor but different subtypes.
• Example: Epinephrine binds varying adrenergic receptor subtypes.

Opioid Receptors

• Main activity goes through the Mu opioid receptor (MOR).
• Other receptor subtypes include delta and kappa opioid receptors.
• Changes at the R2 position can affect binding activity at the MOR.
• Increased size and bulkiness at the R2 position improved MOR binding without affecting DOR or KOR.
• Adding a polar nitrogen decreased selectivity because it improved binding at the off-target receptor subtypes.
• Great selectivity, receptor subtype selectivity for the opioid receptor, potency, and efficacy are promising.

Mode of Action

• Small changes in SAR, with the core almost intact, may change the mode of action.
• Morphine is converted from an agonist to an antagonist with changes at its N-methyl group.
• GPCRs have flexible conformations and flexible binding partners that can easily alter the mode of action of drugs - SAR should be systematic.

Optimizing Leads

• Cyclic AMP assays help understand signaling from CXCR6 (G protein arm and beta arrestin arm).
• Closing a flexible amide onto a ring can improve ADME and activity.
• Adding a basic nitrogen increases water solubility and improves activity.
• Bioisosteres can improve properties while keeping or improving activity.
• Decorating the benzothizo ring with an electron withdrawing group led to the highest gains in activity.

Assessing Drug-like Properties

• Drug development projects assess drug-like properties as well as receptor activity.
• Key assessments include selectivity, functional activity, ADME, and toxicity.
• Assess current drugs to find potential clinical drugs.

Pharmacokinetic SAR

• SAR includes activity at the receptor and pharmacokinetics.
• SAR can be used to improve metabolic stability, bioavailability, and in vivo efficacy.

Small Molecules vs. Biologics

• Small Molecules:
  • Optimization by SAR is possible.
  • Can improve bioavailability.
  • Can be made oral.
  • Usually no immune reaction.
  • Stable formulation (e.g., a pill).
  • More cost-effective, much cheaper.
  • Can be used in a wider population.
• Small molecule drugs have certain advantages that have traditionally made them the favorites for drug development.

Conclusion: The Critical Role of SAR in Drug Development

• Hone in on the mode of action and confirm it.
• Increase receptor specificity and selectivity through SAR.
• Add in activity for other assays, PK properties, and in vivo activity.
• Select the clinical candidate at the end of an SAR program.