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Why are many drugs aromatic heterocycles?

To the non-specialist in medicinal chemistry (like myself), the abundance of drugs that contain aromatic ring moieties, usually with heteroatoms like N, is somewhat surprising. In fact, in 2012, the top 4 out of 5 drugs by sales contain such groups. 

There are at least a few good reasons why these types of compounds appear so often:

1 Heterocyclic systems are easier to prepare synthetically than all-carbon based aromatic systems and they are easier to modify later.

2  Scaffolds with heterocycles allow the easy introduction of H-bond donors and acceptors to fine-tune the properties of the compound, like binding affinity, solubility, and resistance to metabolism in vivo.

3 Can “template hop” easily off of aromatic ring scaffolds to evolve new IP with the same functionality as a known drug (e.g., Viagra to Levitra).

Can synthetic chemistry specialists give more reasons?  (Post in the comments!) 

Source:  Jordan, A, Roughley, S.  “Drug discovery chemistry: a primer for the non-specialist.”  Drug Disc Today, 14. 2009

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Antifungals and the urgent need for biofilm-specific drugs

Last year I had the opportunity to help write a business plan for a startup company that is taking on a very difficult challenge: finding novel antifungal treatments that target the biofilm, rather than free-living, form of fungal infections.

This is important because recent estimates by the NIH indicate that biofilms are responsible for over 80% of all microbial (bacterial and fungal) infections. For both structural and genetic reasons, biofilms are inherently resistant to antimicrobial therapy and host immune defenses.

Systemic biofilm infections are most frequently seeded from biofilms formed on mucosal surfaces or implanted medical devices, such as catheters. In fact, biofilm-based infections on catheters are the most serious and prevalent life-threatening consequence of biofilms, resulting in systemic invasive infections.

Existing antifungal drugs aim to kill C. albicans, a major fungal pathogen of humans, but they have significant disadvantages:

1) Inefficient at eradicating C. albicans existing in the resistant biofilm-form.

2) Disrupt the intricate microbial balance within the gastrointestinal tract, allowing for other microorganisms to flourish.

3) Can cause nephrotoxicity in the dosages required to have some effect on the biofilm.

Current treatments for fungal biofilm-based infections are ineffective at destroying the biofilm reservoir, and novel therapeutics specifically designed to target the biofilm are desperately needed to treat these prevalent infections.

In a ground-breaking 2012 Cell paper, Nobile and colleagues identified the transcriptional network controlling the process of C. Albicans biofilm formation.  It consists of six transcriptional regulators and over 1,000 target genes (40 of which are predicted to be highly druggable).

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Importance of list comprehensions in Python

A beginner to python programming is usually taught to use for loops to do a lot things. The temptation  is to bust out a for loop whenever you need to modify a list or string object, but this quickly leads to complex “loops within loops” code architectures that are hard to read (by humans), even though they may work OK.

A simple example:

>>>test_list = [2,4,6,8]

>>>for x in test_list:

…     new_list.append(x  + 1)

>>>new_list

[3,5,7,9]

A better approach is to take advantage of Python’s built-in list comprehension expressions, with the form ‘x for x in y’.

Example:

>>>new_list = [x+2 for x in test_list]

>>>new_list

[4,6,8,10]

This can be expanded to include conditionals, for example:

>>>stripped_list = [line.strip() for line in line_list if line !=””]

You can also loop over multiple elements like this:

>>>seq1=’abc’

>>>seq2=(1,2,3)

>>>[(x,y) for x in seq1 for y in seq2]

[(‘a’,1),(‘a’,2),(‘a’,3),(‘b’,1),(‘b’,2)….(‘c’,3)]

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Practical Fragments: Natural Products as Fragments

There’s an interesting post at Practical Fragments regarding how natural products have been assembled into a small fragment library for screening and lead selection.   Natural products appear to have some advantages over synthetic fragments, including their “3D-ness” and the fact that they were screened by evolution to be protein-binders.

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Important to use deuterated buffers in small molecule NMR

One way to make your life massively easier if you are doing NMR of small molecules, especially at low concentrations (sub-1mM), is to simply work out what buffer you’d like to use and then order all of the components in deuterated form ahead of time.

For example, if you would like to study your molecule in a buffer like HEPES with 5% DMSO, you can order fully-deuterated HEPES and DMSO from companies like CIL and Sigma-ISOTEC.  Although expensive, the time it can save you at the spectrometer and the enhanced quality of the data are likely worthwhile tradeoffs.

You can also go a step further and prepare your buffers in 100% D2O, making water suppression vastly easier and improving the quality of your spectra. These steps work together in a synergistic manner to dramatically improve your data quality when acquiring on small molecules at low concentrations.