Small Molecule Interactions & Peptidomimetic Design

Posted on Feb 21, 2025 in Biotechnology

Small Molecule Interactions with Biomolecules

  • H-Bonds
  • Pi-pi-interaction
  • Electrostatic interaction
  • Hydrophobic interaction

Peptide Drawbacks as Drug Candidates

  1. Major drawbacks of peptides as drug candidates:
    • Biologically unstable
    • Poorly absorbed
    • Rapidly metabolized
    • Poor pharmacokinetics
    • Poor transport properties
    • Rapid excretion

Drawbacks of peptides: bioavailability and pharmacokinetics.

  1. Suggest three ways to improve the pharmacokinetic properties of peptidomimetics.

Peptidomimetics: Mimicking Peptides

A peptidomimetic is a small protein-like chain designed to mimic a peptide. They typically arise from the modification of an existing peptide. The goal of developing peptidomimetics is a non-peptidic molecule derived from a peptide.

Transforming Peptides

  • Side chain modifications
  • Bridging
  • Cyclizations
  • C (alpha) modifications
  • Alpha to beta to gamma amino acids
  • Bioisosteric replacement of backbone fragments
  • Scaffold replacement

Single modification at a time (These modifications involve changes to the peptide that will not occur naturally)

  • Incorporation of non-natural amino acids
  • Backbone mimicry
  • Backbone extension
  • Conformational restriction

Short Summary:

  • Identify the pharmacophore
  • Remove the scaffold
  • Replace scaffold while keeping the pharmacophore
  • Done.

In Silico Structural Proposals

  1. Name three applications to obtain novel structural proposals in silico:
    • Fragment-based drug design
    • Ligand-based drug design – molecular similarity (Pharmacophore development)
    • Structure-based drug design – molecular complementary (use of Xray data of protein)

Pharmacophore Explained

  1. Explain what a Pharmacophore is, and where it can be used.

A pharmacophore is the 3D-arrangement of structural features of a ligand beneficial for ligand-target interaction.

Comparing 3D-pharmacophores allows for scaffold replacement

  • While keeping the biological effect
  • Which leads to novel IP (scaffold hopping)

Bind antibodies, enzymes, transporters, receptors

Es kann eine Reaktion auslösen, oder eine Struktur blockieren

Scaffold Requirements

  1. Name three requirements for a successful scaffold

Cells are often implanted or ‘seeded’ into an artificial structure capable of supporting three-dimensional tissue formation. These structures, typically called scaffolds, are often critical, both ex vivo as well as in vivo, to recapitulating the in vivo milieu and allowing cells to influence their own microenvironments. Scaffolds usually serve at least one of the following purposes:

  • Allow cell attachment and migration
  • Deliver and retain cells and biochemical factors
  • Enable diffusion of vital cell nutrients and expressed products
  • Exert certain mechanical and biological influences to modify the behaviour of the cell phase

To achieve the goal of tissue reconstruction, scaffolds must meet some specific requirements. A high porosity and an adequate pore size are necessary to facilitate cell seeding and diffusion throughout the whole structure of both cells and nutrients. Biodegradability is often an essential factor since scaffolds should preferably be absorbed by the surrounding tissues without the necessity of a surgical removal. The rate at which degradation occurs has to coincide as much as possible with the rate of tissue formation: this means that while cells are fabricating their own natural matrix structure around themselves, the scaffold is able to provide structural integrity within the body and eventually it will break down leaving the neotissue, newly formed tissue which will take over the mechanical load. Injectability is also important for clinical uses. Recent research on organ printing is showing how crucial a good control of the 3D environment is to ensure reproducibility of experiments and offer better results.

Scaffold Requirements:

  • Good ADME (Absorption, Distribution, Metabolism, Elimination) starting point
  • Substituent diversity
  • Chemical accessibility
  • Pharmacophoric requirements
  • Novelty and patentability
  • Geometrical requirements

Geometrical Requirements:

  • Avoid clashes with receptor
  • Good binding interaction
  • Good vector orientation
  • Understand SAR development as crucial part of the drug discovery process.

Structure-Activity Relationship (SAR)

Building a SAR (structure-activity- relationship): Hypothesis testing with molecules

  • Every molecule has to test a hypothesis
  • Removing, adding or replacing molecular fragments
  • One change at a time relative to a reference compound

Machst SAR und schaust die Nanomolaren bindungsbereich (IC50) (je runter du kommst, umso besser bindet es)

Molecular Interactions for Ligand Design

  1. Use molecular interactions for the design of novel ligands.

Rational Design Process in Drug Discovery

  1. Understand the rational design process in drug discovery.

Start with validated biological target

  • Analyze the structural specificity of target
  • Design drug candidate for optimal interaction