Category Archives: Chemistry

Understanding Multivalency (aka Avidity)

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Making a Ligand or Drug multivalent is a common method to try to improve the potency or EC50 of that drug from that predicted by the Hill Equation. Below we summarize the full spectrum of multivalent enhancement for the n = 2 case (n being the degree of multivalency) but these rules are easily extendable to the n-valent case aswell.

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The Thermodynamic Limits on Small Molecule Drug Affinity

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Not too long ago, some really cool papers1,3 sought to examine “The Maximal Affinity of Ligands” by compiling a list of known small-molecule drugs and comparing their affinities (in kcal/mol or Kd‘s see post on the Hill Equation) with various parameters such as molecular weight (see figure above).1

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Kinetic Limits on Engineering Agonist Drugs

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There are many drugs that act as agonists ligands (L) which means they “turn on” their target receptor (RL) so that it induces its normal down-stream signalling. Examples of such drugs include: growth hormones, insulin, steroids and G-protein coupled Recetor(GCPR) ligands such as morphine (opiods), neurotransmitters and scent/aroma compounds. In general you can improve the potency (EC50) of these drugs by improve their binding dissociation constant (Kd) for their receptor (for more detail see post on the Hill Equation).

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How High are HOMO’s and Low are LUMO’s?

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The energies of a molecule’s Highest Occupied Molecular Orbital’s (HOMO’s) and the Lowest Unoccupied Molecular Orbitals (LUMO’s) tell us alot about that molecules reactivity. In general, molecules with high HOMO’s are good nucleophiles, bases, and reductants while molecules with low LUMO’s are good electrophiles, Lewis acids and oxidants. Unfortunately, the absolute magnitudes of “high” or “low” are very rarely treated. In the figure above, we plotted absolute values of HOMO and LUMO energies to convey more of a global understanding of reactivity trends.

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A Single pKa Chart: Visualizing Reactivity Trends

Figure 1 A. Chemical Functional Groups organized by pKa (y-axis) and acidic atom (x-axis: oxygen, nitrogen, carbon, other.)  B. Key for using A given a solution pH. First, mark the position of the solution pH on the pKa axis (dotted horizontal line). all functional groups above it are neutral or positively charged while all functional groups below it are negative or neutral. Second, the pKa axis is useful in further categorizing functional groups by their ability to participate in hydrogen bonds.

The pKa value of a chemical functional group (Figure 1A) is very useful because it can directly give you the approximate charged state of that functional group (in the context of drugs, proteins, membranes, DNA, etc.) at a specific solution pH.  As such, the pKa is critical to an intuitive understanding of electrostatics in chemical and biological contexts.

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