Pushing Boundaries in Small Molecule Prediction

Author: Jonathan Betts

Welcome to edition XV of Structural Strategies, our take on the confluence of data, science, technology, and business in the world of molecular structure.

A Nobel October: Science at the Forefront

A lot has happened since the Nobel Prizes were announced last month, highlighting groundbreaking advances in protein folding and artificial intelligence (AI). Geoffrey Hinton, the "godfather of AI," and John Hopfield received the 2024 Nobel Prize in Physics for their pioneering work on artificial neural networks. Meanwhile, the Nobel Prize in Chemistry recognized David Baker, Demis Hassabis, and John Jumper for their contributions to protein design and the prediction of complex protein structures. These accolades celebrate achievements in areas that resonate deeply with the scientific and business communities.

Pushing Boundaries in Small Molecule Prediction

When will the Nobel spotlight shine on those advancing the science of small molecule (SM) structure prediction? The results of the latest Crystal Structure Prediction (CSP) Blind Test suggest we may not be far off. This program challenges researchers to predict 3D structures from chemical composition alone—a task complicated by the diversity of chemical space and the precision required to predict polymorph stability. While small molecules might seem simpler than proteins, their crystallography demands even greater accuracy.

The CSP Blind Test is a remarkable charitable initiative by the CCDC, which invests its expertise and resources to drive progress in structural science. You can explore the results and their implications here.

The Case for Data in Drug Discovery

A recent review in Nature Computational Science underscores a critical insight: the future of machine learning (ML) in drug discovery hinges on data quality. The review highlights key challenges, including the poor generalization of ML models to data outside their training distribution and biases in existing datasets. The authors conclude that progress in ML depends as much on refining data and validation methods as it does on algorithmic sophistication.

This call to action is particularly timely as the pharmaceutical industry grapples with regulatory changes like the Inflation Reduction Act (IRA) in the U.S., which allows Medicare to negotiate drug prices. While small molecule drugs face pricing restrictions after nine years (compared to 13 years for biologics), early analysis by Andrew Pannu suggests that investment in SM therapies hasn’t yet suffered significantly. However, the long-term effects remain uncertain. Read more.

Navigating Uncertainty: U.S. Policy and Global Implications

The outcome of this month’s U.S. elections could have wide-ranging impacts on science and business. While a reversal of the IRA seems unlikely, companies may pivot to focus on biologics investment and adopt new strategies to address small molecule pricing challenges.

At the same time, the U.S. is embracing policies to boost domestic energy production, creating mixed consequences. While energy-intensive sectors like AI may benefit from reduced costs, the environmental trade-offs are stark. Meanwhile, the UK’s commitment to Net Zero policies leaves its industries at a comparative disadvantage, with energy costs up to five times higher than in the U.S. (Financial Times analysis).

Sustainability in Focus

If sustainability is as much your priority as structural science, take a look at Peter Smith’s insightful Procurement with Purpose newsletter. It highlights innovative efforts like Imperial College’s lab sustainability initiative, where energy, reagent, and waste reduction strategies are transforming the operational footprint of 1,400 labs. Learn more.

Bridging Experimental and Computational Methods

A recent collaboration between CCDC and Pfizer demonstrates the power of integrating experimental, informatics, and energy-based methods in drug development. Their publication explores how these approaches can reduce risks and improve predictions of stable solid forms—key to advancing from molecule to medicine. Discover more.

Looking Ahead

As we approach the end of 2024, our industry continues to evolve at a rapid pace. For those interested in material design outside the traditional pharmaceutical sector, don’t miss the upcoming CCDC webinar on functional materials—a fascinating field blending molecular design with electrical and optical properties. Register here.

In structura veritas.