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Related Concept Videos

Drug-Receptor Bonds01:25

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Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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The receptor occupancy theory connects a drug's response to the number of occupied receptors. With higher drug concentrations, more receptors are occupied, leading to increased responses. The formation of drug-receptor complexes involves association and dissociation rates, which reach equilibrium when the forward and backward reactions are equal. The equilibrium association constant (Ka) and its inverse, the equilibrium dissociation constant (Kd), indicate drug affinity. Higher Ka and lower...
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Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
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Updated: Sep 18, 2025

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
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Diffusion Limit and the Reactivity/Affinity Conundrum: Implications for Optimization and Hit Finding for Irreversible

Bharath Srinivasan1,2,3

  • 1School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen AB10 7AQ, U.K.

Journal of Medicinal Chemistry
|June 25, 2025
PubMed
Summary
This summary is machine-generated.

Targeted irreversible inhibition drug design faces a physical limit. Increasing small molecule affinity for better binding also reduces reactivity, impacting drug development for difficult targets.

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Area of Science:

  • Medicinal Chemistry
  • Chemical Kinetics
  • Drug Discovery

Background:

  • Irreversible inhibition is a key therapeutic strategy, gaining prominence in the last decade.
  • Current drug design often balances small molecule affinity with electrophile reactivity to minimize off-target effects.
  • Limited theoretical frameworks exist for designing effective irreversible inhibitors.

Purpose of the Study:

  • To challenge the conventional approach in irreversible inhibitor design.
  • To propose a kinetic limit for the inactivation rate constant over the inhibition constant (k_inact/K_I).
  • To explore the implications of this kinetic limit on drug discovery and optimization.

Main Methods:

  • Kinetic analysis of irreversible inhibition.
  • Theoretical evaluation of rate-limiting steps in molecular interactions.
  • Discussion of implications for drug design strategies.

Main Results:

  • The inactivation rate constant over the inhibition constant (k_inact/K_I) is physically limited by diffusion rates.
  • Attempts to enhance small molecule affinity at this limit necessitate a trade-off in reactivity.
  • This kinetic capping affects hit finding and lead optimization for irreversible inhibitors.

Conclusions:

  • The design of irreversible inhibitors is constrained by fundamental kinetic principles.
  • Optimization strategies must account for the diffusion-limited trade-off between affinity and reactivity.
  • This understanding is crucial for developing drugs against challenging targets, particularly those with shallow binding pockets.