We all knew process scientists were good, but the Merck and Codexis teams just took it to another level!  Unnatural nucleosides like Merck’s reverse transcriptase inhibitor islatravir ( 1 , Figure 1) are well-known to be challenging to synthesize by traditional methods, as evidenced by several published chemical syntheses [...]

This table features a selection of some of the best drug discovery journals. While not exhaustive (our team’s RSS feed includes hundreds), this is a subjective list of where to find the most valuable articles for those entering the field.

You’ve probably lived this story before: you’re working on your favorite kinase, YFK1, and are looking for selective inhibitors over YFK2.  The problem is, they’re virtually identical near the active site, save for a single residue sitting in the back pocket that your amazing structural biologist has identified.  The team [...]

Having a clinical drug-induced liver injury (DILI) signal is a surefire way to kill a drug candidate in non-serious indications like pain or chronic indications like diabetes, and will even give oncologists second thoughts as cancer patients are living longer. What can we do to prevent it? Plan A: Small Pill and No Greaseb ombs A widely [...]

Protein-ligand interactions are driven predominantly by strong hydrogen-bonding interactions, de-solvation energetics, and other entropic considerations including ligand lipophilicity. However, the combination of many weaker interactions can contribute to potency, and are often necessary to obtain selectivity when targets and anti-targets [...]

The C-H --- O hydrogen bond is so well established in structural biology today, that it's been overlooked that the C-H --- O hydrogen bond was first proposed by a woman, June Sutor, in a 1960's Nature article.[1] Hydrogen bonds were then assumed to be linear (A-H···A’ between 150-180º), and the C-H --- O hydrogen bonds proposed by Sutor are [...]

With the biochemistry magic available to the liver, it's a wonder that anything we consume is well-tolerated. Even carboxylic acids are structural alerts as they can be converted to bioreactive acyl glucoronides. The best we can do as drug hunters is minimize the risk of toxic metabolite formation and apply assays appropriately to select [...]

There are catalysis geniuses (looking at you, process chemists!) and then there are those of us just looking to put compounds in vials.  Here are the simplest conditions that'll get you what you want 90% of the time.  Beyond that you'll need to ask a guru like Nick White or Malcolm Huestis. Hope this table helps. Explore drughunter.co m for more.

The global cancer immunotherapy pipeline continues to explode with nearly double the number of active targets in 2019 vs. only two years ago, comprising 3,876(!!) active drugs, with a subset undergoing >5000 active clinical trials. In 2016, I listened to Dan Chen, former Global Head of Cancer Immunotherapy Development at Genentech, comment on [...]

Scientists from GlaxoSmithKline’s Stevenage site have an excellent article in J. Med. Chem. showing that cyclopropyl pyran (CPP) groups can serve as viable isosteres to N-pyrimidyl morpholines thanks in part to favorable cyclopropane σ -> aryl π interactions. N -aryl morpholines are privileged motifs in drug discovery, and suitable [...]

Of the record 59 FDA drug approvals from 2018, the majority were small molecules (64%). Keep at it, chemists! :) Oncology and infectious diseases were the areas with most small molecule approvals, followed by genetic/rare diseases. Some more statistics below. Last year the FDA approved a record 59 novel drugs , which included 38 small [...]

Modern hit-finding technologies are incredible. Dean Brown and Jonas Bostrom at AstraZeneca have a very nice review out summarizing the hit-finding strategies for 66 clinical candidates published from 2016-2017. Some highlights include a clinical candidate from DNA-encoded libraries at GSK, the discovery of an RNA-binding drug candidate by [...]

BMS-986142 is a reversible BTK inhibitor with two axial stereocenters.  BMS synthetic chemists were able to make >200 kilos of this compound as a single isomer using this route.  Wow. Atropisomers are a nightmare in drug discovery.  Axial stereocenters are not easy to set predictably, separation of isomers is a pain, and the products are hard [...]

Checkpoint inhibitors like pembrolizumab (Keytruda) have revolutionized treatment for many late-stage cancer patients, including Jimmy Carter. Recently, Keytruda stunned the world again with efficacy in metastatic non-small cell lung cancer, the leading cancer killer. Here's a summary of its recent successes and the surprising path Keytruda [...]

Knochel's group has shown that you can fluorinate Grignard reagents without decomposition via single-electron transfer reactivity (SET) by a simple solvent switch from THF to DCM. A common way to prepare aryl fluorides is through lithium-halogen exchange, followed by trapping with N-fluorosulfonimide (NFSI).  This isn't always viable, as the [...]

Gleevec (imatinib) was the first tyrosine kinase inhibitor approved for the treatment of cancer and one of the first products to emerge from "rational drug design."  It's invention changed chronic myeloid leukemia from an incurable death sentence to a manageable disease. Here's a look back on the tremendous value it's created over the last [...]