Category Archives: Chemistry

Introduction to Fluorescence

07 Fluorescence Introduction

Fluorescence (i.e. the emission of light from a electronically excited substance) is one of the most utilized physical phenomena in chemistry and biology. Though humans have been aware of fluorescence for thousands of years (e.g. fireflies), it wasn’t until the discovery of quinine in 1845 that we really started to understand its chemical basis(see figure above). Interestingly, during World War II, the study of quinine’s anti-malarial properties led to the development of the first spectrofluorometers which enabled true quantitative study of fluorescence. Finally, in the 1980-1990’s, new tools in synthetic chemistry and molecular biology allowed rational engineering of chemical fluorophores into a critical class of probes in biophysics(microscopy), molecular biology(sequencing), cell-biology(flow cytometry) and even anatomy (histology)).

Continue reading

Understanding Multivalency (aka Avidity)

Web

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.

Continue reading

The Thermodynamic Limits on Small Molecule Drug Affinity

Web

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

Continue reading

Kinetic Limits on Engineering Agonist Drugs

kinetic-limits-on drug-design-v1

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).

Continue reading

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

Print

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.

Continue reading

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.

Continue reading