Structural relationships for receptors and ligands (2023)

This chapter is relatedto the aimsof SectionC(iv) from the2017CICM Primary Syllabus, whichexpects theexam candidate to"explain receptor activity with regard to...structural relationships for receptors and ligands". What precisely they mean is difficult to guess,in the context of assessment-driven learning(given that it has never come up in the exams before and we don't even have a rude examiner comment about how much the answers sucked). Given the wording and intentions of the curriculum, one can make best guess estimates of what might be important. This chapter represents a series of such guesses.

Using one's imagination, it would seem from from the way the learning objective is wordedthat the college wanted trainees to know something about the ways in which receptor structure and ligand structure influences their interaction. This is something fairly fundamental to biology in general. "Highly specific molecular recognition is one of the fundamental principles of functioning of living systems",starts a biomedical engineering article byGuryanovet al (2016).Clearly, the discussion of something like that is probably outside of the scope of an Intensive Carepharmacodynamicssyllabus.

As far as finding peer-reviewed published literature on the subject, the pickings are slim. Indeed, if one googles the phrase "structural relationships for receptors and ligands",the only search result is the CICM2017 syllabus document (i.e. in all human written communication this combination of words has never been usedbefore). That makes it difficult to track down anything useful as a point of reference, even to begin writing a structure for this topic. Fortunately, there is a whole textbook on the general topic. Phillip Michael Dean'sMolecular Foundations of Drug-Receptor Interactionis probably the definitive text, albeit somewhat dated (1987). Some recently updated and scaled-down versions of the same material can be found in reviews such as the oneby Pierre Bongrand (1999). Because Dean's book is out of print, one might instead need to use something like Steed and Atwood'sSupramolecular Chemistry(mine is the 2nd edition from 2009).

Given the vagueness of the learning objectives and the absence of historical SAQ examples, this is an unlikely question topic. Having said that, weirder things have been asked about (endothelial glycocalyx, seriously). Ergo, a short summary is left here for the primary exam candidates who should only want to develop a very superficial grasp of this topic.

  • Ligands are usually small molecules; but they range fromions andsmall peptides to dissolved proteins.
  • Receptors are usually large proteins with complex 3D structure
  • Receptors and ligands have molecular complimentarity:i.e. the shape and chemical properties of their binding sites are matching to permit high-affinity selective binding.
  • The chemical bonds which mediate their interaction are:
    • Van der Waals forces (most important for highly complimentary molecules, for example monoclonal antibodies and their targets)
    • Hydrophobic attraction (eg. sugammadexand rocuronium)
    • Hydrogen bonding (binding of a local anaesthtic to a voltage-gated sodium channel).
    • Electrostatic attraction,eg. acetylcholine and its receptor
    • π–π "stacking" interactions between aromatic rings orπ– cation interactions, eg. neurotransmitters such as dopamine
    • Rarely, a receptor and a ligand will bond covalently (a "suicide" bond - eg. phenoxybenzamine)
  • The specificity of receptor and ligandbinding forms one of the elements of a drug'spharmacophore- the "ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target"

Pharmacophore

Paul Ehrlich's first definition of the pharmacophore, from his 1909 "Über den jetzigen Stand der Chemotherapie", was as follows:

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"Amolecular framework that carries (phoros) the essential features responsible for a drug’s (pharmacon) biological activity".

The more recent 1998 IUPAC definitioncontainsslightly scienced-up language, but remains essentially unchanged in spirit:

"An ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response"

As such, apharmacophoreis not a real molecular structure like an OH side group or a disulfide bond; it is an abstract concept which describesall the properties which account for the ability of one molecule to specifically recogniseanother molecule,and with a high affinity bind it. Of these properties, the molecular structure and shape of the binding regions is probably the most important factor.

The concept of molecular complimentarity

The term "molecular complimentarity" describes the matching of surface shape and chemical properties between receptors and ligand molecules. It is essential for high-affinity bonds to form. Both the surface structure and the chemical properties of the ligand-binding site must fit the ligand like a lock fits a key.

The keyhole is small.The contact surface which iscomplimentary to the ligand molecule may be in the order of several hundred to several thousandsquare Angstrom (Å2).Bongrand (1999)offers some examples from biology. For instance, the contact surface between a T-cell HLA A2 receptor and its viral oligopeptide ligand was 1,011Å2.

Structural relationships for receptors and ligands (1)

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The lock and key imagery actually dates back to the early 20th century; the concept has now evolved into the "induced fit" theory (Koshland, 1994) which describes a more complex process, one with several possible stages. The ligand and receptor first interact weakly at a distance, then both change shape, interact more strongly, and finally bind.

Not all ligand molecules are specific for unique receptors. There exists a number of "privileged scaffolds", molecular structures which seem to act as ligands for a whole array of receptors (Welsh et al, 2010). These include such examples as the quinolinerings (the reason for why hydroxychloroquine is both an antimalarial agent and an immunosuppressant).

Molecular characteristics of ligands and receptors

Ligands can be any damn thing. They could be an ion (eg. sodium or calcium), a small molecule (ethanol), a small peptide (vasopressin) or a large peptide (insulin) or a protein (infliximab).

Receptors are generally alarge protein with a complex structure.A receptor is defined by Goodman And Gilman as

"the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response"

This is in contrast to a drugacceptorsuch as albumin, to which the drug binds with no discernable physiological effect. Only the pharmacokinetics of the drug are altered by this acceptor binding.

Receptor-ligand chemical interactions

Receptors and ligands connect via a variety of bonds, ranginng from fairly weak (like Van Der Waal and hydrophobic bonding) to very strong (covalent, "suicide" bonds). Apart from the latter, these are not firm and irreversible associations. Rather, it can be said that at any given time there are some ligand molecules bound and some unbound, and that the higher the affinity of the receptor for the ligand the greater the bound proportion.

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The bonds in a bit of detail:

Van der Waals forcesare attractive forces resulting from the polarisation of an electron cloud by the proximity of an adjacent positively charged nucleus, resulting in a weak electrostatic attraction. The amount of force is vaguely proportional to the available area for contact, i.e. themore electron clouds and nuclei there are to interact the greater the total force. It also diminishes rapidly with distance.

Structural relationships for receptors and ligands (2)

These forces are probably the weakest of all the forces responsible for drug-receptor interactions. However, they are probable also the most important for high specificity. Because of their dependence on shortdistances, these forces can only really take effect when the surfaces are in close apposition, i.e. when the molecules are highly complimentary. Examples of such highly complimentary pairings would have to include such agents as monoclonal antibodies.

Hydrophobic forcesproduce bonding because of the exclusion of poorly solvated complexes from pools of polar solvent. In general water molecules bind each other with high affinity and in a body of water they will all tend to be strongly attracted to one another. Non-polar molecules will end up being pushed out of the way of strongly attracted water molecules as they crowd together.Non-polar neighbours will end up being pushed together by this effect; it is demonstrated by the immiscibility of oil in water (the oilmolecules end up being pushed together into blebs).

Structural relationships for receptors and ligands (3)

This effect can give the impression of attraction, but in fact the receptor and ligand have no chemical affinity for one another. This effect has several examples, for instance the binding of organic guests such as rocuronium by cyclodextrin hostssuch as sugammadex. The inside of the cyclodextrin cavity is highly non-polar, and the hydrophobic muscle relaxant molecules huddle in there,seeking refuge from the watery environment outside.

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Structural relationships for receptors and ligands (4)

Hydrogen bondsare a kind of dipole–dipole interaction where a hydrogen atom is attracted to a dipole on an adjacent molecule. A hydrogen bondisstronger than hydrophobic or Van Der Waals forces. This is illustrated by the fact that highly hydrogen-bonded H2Ohas a boiling point of 100° C, and the non-hydrogen-bonded H2S has a boiling point of -60° C. This is one of the bonds which facilitates the binding of a local anaesthetic to a voltage-gated sodium channel.

Electrostatic interactions are simple interactions between opposing charges as described by Coulomb's law. This is how the quaternary amine (N+) of acetylcholine and suxamethonium binds in this manner to the anionic active site of the acetylcholine receptor (Harel et al, 1993).

π-π interactions describe"stacking"of aromatic rings, which occurs often in situations where one is relatively electron rich and one is electron poor. Examples of this effect taking place include thespontaneous helical curlingof the DNA double helix and the binding of dopamine to its target site (Nishihira et al, 1997). In fact many neurotransmitters bind to their receptor sites byπ-π orπ-cationinteractions.

Structural relationships for receptors and ligands (5)

Covalent bondingis mentioned here because itis one of the more interesting ways receptors and ligands can interact in clinical chemistry, of interest to the intensivistparticularly because it is often something very dramatic. Particular examples include phenozybenzamine, a potent α-1 antagonist which binds covalently to the α-1 receptor. It is used in the management of phaemochromocytoma.

FAQs

What are the main types of bonding interactions between ligands and receptors? ›

Receptors and ligands connect via a variety of bonds, ranginng from fairly weak (like Van Der Waal and hydrophobic bonding) to very strong (covalent, "suicide" bonds). Apart from the latter, these are not firm and irreversible associations.

How do ligands interact with their receptors? ›

When a ligand binds to a protein, it undergoes a conformational change which in turn leads to a physiological response. The time a ligand spends attached to a receptor or specific protein is a function of the affinity between the ligand and the protein.

What are receptors and ligands How are they significant in drugs? ›

Receptor is a macromolecule in the membrane or inside the cell that specifically (chemically) bind a ligand (drug). The binding of a drug to receptor depends on types of chemical bounds that can be established between drug and receptor.

What are the three 3 major types of drug receptor bonds? ›

The three major types of bonds are covalent, electrostatic, and hydrophobic.

What type of receptor binds to ligands? ›

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal.

What is the relationship between the ligand and the receptor protein to which it will bond during chemical signaling? ›

Receptors are a special class of proteins that function by binding a specific ligand molecule. When a ligand binds to its receptor, the receptor can change conformation, transmitting a signal into the cell. In some cases the receptors will remain on the surface of the cell and the ligand will eventually diffuse away.

How do ligands activate receptors? ›

A ligand binds to the extracellular domain (ECD) and activates the receptor. The signal then transmits into the intracellular domain (ICD) through the transmembrane domain, and stimulates a cascade of events inside the cell.

What is the relationship between a ligand structure and its mechanism of action? ›

When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response.

How do you identify a ligand for a receptor? ›

Specific receptors for the ligand of interest are identified through quantitative comparison of the identified peptides with a sample generated by a control probe with known (e.g., insulin) or no binding preferences (e.g., TRICEPS quenched with glycine).

Are receptors also called ligands? ›

Within biochemistry, a ligand is defined as any molecule or atom that irreversibly binds to a receiving protein molecule, otherwise known as a receptor.

What is the importance of a ligand? ›

Ligands play multiple roles ranging from the regulation of the solubility and availability of active components during NP synthesis to the post synthetic minimization of surface energy of NPs (required for their colloidal stability) as well as the encoding of NP functionality.

What happens to cell receptors when they bind to a ligand quizlet? ›

Binding of a ligand to a receptor causes a conformational change in the receptor that initiates a sequence of reactions leading to a specific response inside the cell.

What are the different forces that affect drug receptor interaction? ›

The forces that are important in the binding of drugs to receptors include, electrostatic attractions and van der Waals forces (e.g., hydrogen bonds5 and dipole-dipole forces) (Figure 9).

Why is structure activity relationship of drugs important? ›

Structure-Activity Relationship (SAR) is perhaps the most important concept in drug development. Medicinal chemists can “read” SAR like a travel guide. Establishing SAR informs precisely those positions on a molecule where one can modify, to improve certain properties, including: solubility.

What are the important factors influencing drug receptor interactions? ›

A drug's ability to affect a given receptor is related to the drug's affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response).

What are some examples of ligands? ›

Examples of common ligands are the neutral molecules water (H2O), ammonia (NH3), and carbon monoxide (CO) and the anions cyanide (CN-), chloride (Cl-), and hydroxide (OH-). Occasionally, ligands can be cations (e.g., NO+, N2H5+) and electron-pair acceptors.

Can receptors bind to multiple ligands? ›

These assemblies, called multi-specific ligands, contain multiple receptor binding sites and are able to target different cell surface receptors simultaneously.

Do receptor molecules bind to all ligands? ›

Ligands interact with proteins in target cells, which are cells that are affected by chemical signals; these proteins are also called receptors. Ligands and receptors exist in several varieties; however, a specific ligand will have a specific receptor that typically binds only that ligand.

Why does a receptors proteins structure change when a ligand binds? ›

These receptor proteins are specific for just one signal molecule. The signaling molecule acts as a ligand when it binds to a receptor protein. A ligand is a small molecule that binds to a larger molecule. Signal molecule binding causes the receptor protein to undergo a conformational change (a change in shape).

What types of interactions a ligand can have with the protein? ›

Among the most frequently observed are interactions that are well known and widely used in ligand design such as hydrophobic contacts, hydrogen bonds and π-stacking. 18,19 These are followed by weak hydrogen bonds, salt bridges, amide stacking, and cation–π interactions.

What are the interactions of ligands with proteins? ›

Protein-ligand interactions are a necessary prerequisite for signal transduction, immunoreaction, and gene regulation. Protein-ligand interaction studies are important for understanding the mechanisms of biological regulation, and they provide a theoretical basis for the design and discovery of new drug targets.

How does a ligand activate a cell? ›

A ligand binds to a receptor, leading indirectly to activation of adenylyl cyclase, which converts ATP to cAMP. cAMP binds to protein kinase A and activates it, allowing PKA to phosphorylate downstream factors to produce a cellular response.

How are ligands removed from receptors? ›

Receptor inactivation can operate in several ways including removal of the ligand by degradation or sequestration, and desensitization of the target cell. Binding of a ligand to its receptor is a reversible process, as the ligand will ultimately dissociate from the receptor and may be degraded.

What is the structure of a ligand? ›

Ligands are ions or neutral molecules that bond to a central metal atom or ion. Ligands act as Lewis bases (electron pair donors), and the central atom acts as a Lewis acid (electron pair acceptor). Ligands have at least one donor atom with an electron pair used to form covalent bonds with the central atom.

Do all ligands have the same chemical structure or shape? ›

No, no two ligands or receptors have the same chemical structure or shape. If all ligands were the same, the signals could be misinterpreted. Because some hormones, such as estrogen and testosterone, contain lipids, they are non-polar.

What forces are involved in protein structure and protein-ligand binding? ›

We show that protein-ligand interactions are governed by different forces for different ligand types, i.e., protein-organic compound interactions are governed by hydrogen bonds, van der Waals contacts, and covalent bonds; protein-metal ion interactions are dominated by electrostatic force and coordination bonds; ...

What are the four types of ligands? ›

Ligands are classified based on the number of lone pair electrons available for the central metal atom, size and charge like anionic, cationic, neutral, monodentate, bidentate, polydentate ligands.

How do you determine the affinity of a receptor towards specific ligand? ›

Binding data analysis provides the affinity of the receptor for the competitor molecule. Kinetic assays are used to determine receptor / ligand pair specific dissociation and association constants. Multiple receptor specific radioligand binding assays protocols have been developed [28].

What are the 4 types of bonding? ›

There are four types of chemical bonds essential for life to exist: Ionic Bonds, Covalent Bonds, Hydrogen Bonds, and van der Waals interactions. We need all of these different kinds of bonds to play various roles in biochemical interactions.

What kinds of interactions exist between a ligand and a protein? ›

Among the most frequently observed are interactions that are well known and widely used in ligand design such as hydrophobic contacts, hydrogen bonds and π-stacking. 18,19 These are followed by weak hydrogen bonds, salt bridges, amide stacking, and cation–π interactions.

What are the 4 types of membrane bound receptors? ›

Receptors can be divided into four basic classes on the basis of their structure and mechanism of action: (1)ligand-gated ion channels, (2)G protein–coupled receptors (GPCRs), (3)enzyme-linked receptors, and (4)nuclear receptors (Table 3.1;Figs.

Which types of chemical bonding is observed between drug and receptors? ›

The drug-receptor reaction is essentially an exchange of the hydrogen bond between a drug molecule, surrounding water, and the receptor site. Finally hydrophobic bonds are formed between non-polar hydrocarbon groups on the drug and those in the receptor site.

What are the types of bonds in relationships? ›

There are three main attachment styles: secure, anxious, and avoidant. These are based on your first bonds as a child. Those with a secure attachment style are generally more trusting and responsive in relationships. People with anxious attachment style tend to put other people's needs before their own.

What are the 3 types of bonds How do they differ between one another? ›

What is the difference between ionic, covalent, and polar bonds? The difference between bond types is simply how they share electrons. Covalent bonds share evenly, polar share unevenly, and ionic bonds don't share at all.

What are the 5 characteristics of a bond? ›

Characteristics of bonds
  • Face value. Corporate bonds normally have a par value of $1,000, but this amount can be much greater for government bonds.
  • Interest. ...
  • Coupon or interest rate. ...
  • Maturity. ...
  • Issuers. ...
  • Rating agencies. ...
  • Tools and tips.

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