One of the key challenges in CNS projects is achieving sufficient unbound brain exposure to engage the target. To predict CNS exposure, scientists employ metrics like CNS MPO scores from Pfizer and Merck, Bayesian models, and methods for balancing physicochemical properties. However, these in silico metrics often fail to correlate well with experimental data. Schrödinger's team has discovered the energy of solvation (E-sol) metric, which accurately predicts Kp,uu and has been validated with CNS-penetrant DLK inhibitors. Explore more in this detailed Drug Hunter article.

Imagine having access to an almost infinite amount of chemical space that could include the next blockbuster medicine waiting to be discovered. The challenge for medicinal chemists is balancing the exploration of this vast space in early drug discovery with the need for focused exploration in later stages. This article explores the genesis of a new AI-powered drug design tool, AIDDISON™ from MilliporeSigma, and how this platform can benefit discovery teams around the world.

With increasingly tight timelines between bench and clinic, considering formulation strategies early on can give your program a competitive edge. This succinct formulations guide provides specific clinically-used examples of common formulations, and can help you select a formulation strategy most likely to succeed based on the properties of your compound.

Targeted Protein Degradation (TPD) allows for elimination, rather than inhibition, of proteins by exploiting cells’ own protein clearance mechanisms. While traditional inhibitors can be very effective at preventing a protein from undertaking a particular function, blocking protein activity...

Small molecule drugs make up most of the drugs we take conveniently as pills, including painkillers like ibuprofen (Advil), antibiotics like penicillin and amoxicillin, or cholesterol-lowering drugs like atorvastatin (Lipitor). The biotechnology revolution allowed scientists to create drugs through genetic engineering and related biological processes, creating a new category of drugs known as “biologics.”...

Macrocyclic molecules, containing 12 or more atoms in a ring system, are increasingly prevalent in drug discovery, with over 67 macrocyclic drugs approved so far and several notable examples of clinical success highlighted on Drug Hunter recently, including MK-0616 , repotrectinib , and pacritinib . By imparting conformational restraint and [...]

Here’s a common scenario - your team has just completed a phenotypic screening campaign, cleaned out the false positives through hit triage , and now you have modestly optimized validated leads with cell-based activity. The problem is, you have no idea how your compounds work, and whether they act on a target or set of targets that are worth [...]

We recently explored how the lipophilicity (logP) of drugs has changed over time and found that, on average, drugs have become more lipophilic through the decades, primarily attributable to the industry’s move away from natural products. Despite this shift, it is clear from a broad qualitative comparison of structures from past decades to [...]

Artificial Intelligence (AI) is revolutionizing data processing, with applications to drug discovery ranging from automating cellular imaging to modeling protein folding . Although numerous startups are developing methods to apply AI-driven drug discovery to develop proprietary assets, a remaining challenge is making these powerful tools [...]

Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs , their bulkier bivalent counterparts, to the [...]

Today, ozanimod is a likely megablockbuster drug approved for ulcerative colitis and multiple sclerosis. But before it became the first S1P modulator approved in ulcerative colitis, it received a scary, headline-making “ Refuse to File ” letter from the FDA due to insufficient preclinical characterization of an active metabolite RP112273 [...]

Drug lipophilicity is a core property that contributes to drug solubility, permeability, metabolic disposition, and other key properties. Increasing lipophilicity can often lead to increased affinity in relevant biological assays due to the hydrophobic nature of many protein binding pockets,  but this may also increase promiscuity to [...]

Drug candidates exhibiting atropisomerism are often considered challenging for development by pharmaceutical professionals from synthetic and regulatory perspectives. Molecules that exist as stable atropisomers can be acceptable for development, but are often difficult to synthesize in their isomerically pure form. Modern catalysis [...]

The real magic happens when chemists can integrate computational models into their assay cascades, thanks to trust in their predictions. To get there, grounding computational predictions in physics and experimental reality makes all the difference. In this article, Abba E. Leffler, Ph.D. from Schrödinger tells us about: How to make [...]

This article explains what Phase II drug metabolism is, contains a poster summarizing common enzyme-mediated bioconjugation reactions, and provides interesting examples of Phase II transformations and their impact on drug pharmacology. "As any biotransformation scientist will know, metabolism is not a binary function, and drugs can be cleared [...]

Optimizing lead compounds to have drug candidate-like qualities is time-consuming and expensive. Oftentimes, critical drug discovery project questions, such as on-target pharmacology or toxicology, can be answered more efficiently with compounds that are "good enough," saving teams time and further resource investment. This article discusses [...]

In this article, we highlight the importance of p K a values in medicinal chemistry and drug discovery and provide a reference poster of p K a values of common amines’ conjugate bases. Since amines are often a part of marketed drugs, knowledge of their p K a s can provide guidance in the selection of basic moieties to match the desired [...]

The gem-dimethylcyclopropyl group is a key element in drugs, candidates, and agrochemicals, with a recent example being nirmatrelvir, the active ingredient in the Pfizer COVID-19 drug, Paxlovid. Here, we review synthetic strategies used to produce the key gem-dimethylcyclopropylproline intermediate, which may now be required in hundred-ton [...]

Small-molecule drug candidates are increasingly falling “ beyond the rule of 5 ,” making oral administration more challenging. Optimizing a drug’s solid form can improve its solubility and bioavailability when further molecular modifications are prohibitive. This minireview covers solid form strategies for increasing the solubility and oral [...]

This article explains what Phase I drug metabolism is, contains a poster summarizing common enzyme-mediated drug metabolism reactions, and provides interesting examples of phase I biotransformations and their impact on drug pharmacology. By Drake Anthony Russell , reviewed by Dr. Dian Su and Dr. Julia Shanu-Wilson. Thanks to Hypha Discovery [...]

Recently our non-profit partner, California Life Sciences , completed nominations for the 2021 Pantheon Award for Scientific Advancement . We’re glad to see several drug hunters and drug discovery companies across the award categories, and we hope you’ll help get some industry drug hunters deserved recognition for their achievements by voting [...]

Afternote: We're pleased to see Dan Erlanson made it as a finalist in the awards and Amgen's sotorasib won " Product of the Year ." Well deserved! Thanks to our readers for voting. Which drug hunters are making the greatest scientific contributions to drug discovery R&D? Our non-profit partner, California Life Sciences , is currently taking [...]