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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
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Drug Discovery: Overview

Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
Drug Distribution: Tissue Binding01:21

Drug Distribution: Tissue Binding

Upon entering the systemic circulation, drugs can distribute into the interstitial and intracellular fluid of various tissue cells. This distribution is facilitated by the binding of drugs to different cellular components within tissues, which may lead to drug accumulation in specific areas. Drugs bound to tissue components serve as reservoirs that release free drugs back into the system, prolonging the drug's overall action. However, this accumulation can also result in local toxicity.
For...
Drug Distribution: Plasma Protein Binding01:29

Drug Distribution: Plasma Protein Binding

Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
Tissue-Drug Binding: Localization of Drugs and its Significance01:24

Tissue-Drug Binding: Localization of Drugs and its Significance

Body tissues, comprising approximately 40% of the body weight, are crucial in drug distribution and localization. These tissues can serve as drug storage sites, competing with plasma binding sites for drug molecules.
Drugs can bind to different tissue components, enhancing their distribution and localization. The factors influencing drug localization in tissues include the drug's lipophilicity, structural characteristics, tissue perfusion rate, and pH differences. These factors determine the...
Protein-Drug Binding: Determination Methods01:22

Protein-Drug Binding: Determination Methods

Determining protein-drug binding can be achieved through indirect and direct methods, each providing valuable insights into the interaction between proteins and drugs.
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...

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Large Library Docking for Polypharmacology.

Yujin Wu1, Seth Vigneron1, Joao Braz2

  • 1Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 fourth St., Byers Hall Suite 508D, San Francisco, California 94158, United States.

Journal of Medicinal Chemistry
|February 19, 2026
PubMed
Summary
This summary is machine-generated.

Large library docking identified dual-activity molecules for complex diseases. While potent compounds were found for pain, depression, and anxiety, challenges remain in optimizing their efficacy.

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Area of Science:

  • Computational chemistry
  • Pharmacology
  • Drug discovery

Background:

  • Polypharmacology, the simultaneous targeting of multiple biological targets, offers a promising strategy for treating complex diseases.
  • Identifying molecules with joint activity against specific target pairs is crucial for developing effective multi-target therapies.

Purpose of the Study:

  • To explore the utility of large library docking for discovering dual-activity molecules against selected target pairs.
  • To identify potential analgesic compounds through prospective docking against alpha2A/SERT, MOR/SERT, and alpha2A/MOR targets.

Main Methods:

  • Retrospective analysis of library growth and dual-activity molecule identification.
  • Prospective virtual screening of a 900-million molecule library using docking against three target pairs.
  • Confirmation of docking-predicted poses using cryo-electron microscopy (cryo-EM) structures.
  • In vivo evaluation of compound efficacy in mouse behavioral assays.

Main Results:

  • Docking campaigns identified dual binders with low μM to high nM activities and high hit rates for alpha2A/SERT and SERT/MOR targets.
  • Tetrahydropyridine compounds from the alpha2A/SERT campaign also exhibited activity against 5-HT2A.
  • Cryo-EM confirmed docking-predicted poses, but subsequent optimization faced challenges in improving potency.
  • The lead alpha2A/SERT compound (z7149) demonstrated efficacy in pain assays without conditioned place preference, and exhibited antidepressant and anxiolytic-like behavior.

Conclusions:

  • Large library docking is a viable strategy for discovering polypharmacological agents, yielding promising hits for complex conditions.
  • Despite structural validation, optimizing the potency of identified dual-activity molecules presents significant challenges.
  • The study highlights both the potential and limitations of computational docking in advancing polypharmacology for therapeutic benefit.