Advancements in Biophysics and Emerging Drug Modalities

As our technology and methods for observing the smallest scales of matter improve, so do our capabilities to characterize molecules – especially complex proteins – with ever greater detail. This grants us the ability to better understand their potential interactions throughout the body, providing the potential to predict their functions and safety profiles with increased precision. The advent of such improved methods has had drastic effects on drug discovery; increased efficiencies in preclinical development techniques can save time, energy and resources that may have otherwise been expended in later stages of clinical development, allowing investigators to focus on the product candidates that truly matter.

Established Methods for Structural Biology

Biophysics has always provided the most powerful tools for molecular observation and description – indeed, some of the most important drug discoveries in recent memory are a direct result of innovations in these tools. The appearance of X-ray crystallography in the 1990s revolutionized the field of drug discovery, allowing for detailed examination of the crystal structures of proteins and the ligands that bind to them. This process enabled colossal improvements in pharmacokinetics and pharmacodynamics, and consequently turbocharged the modern era of structure-based drug discovery. Similar innovations were brought about in structure-based drug discovery with the entry of Nuclear Magnetic Resonance (NMR) spectroscopy into the mainstream. Put together, these have been perhaps the two most important techniques for structural biology up until now.

Cryo-Electron Microscopy

Beyond the two main established methods for structural biology, one new technique stands out in particular: Cryo-Electron Microscopy (cryo-EM). Electron microscopy was traditionally of limited applicability in biological molecules. Even with the advent of cryo-cooling molecules in vitrified water, the technique suffered from low contrast and high noise, making image interpretation exceedingly difficult. These obstacles are now being overcome with the use of computational image processing techniques as well as direct electron detectors, although the minimum size of the molecule being investigated is still well above the possibilities offered by X-ray crystallography. However, cryo-EM offers other advantages – such as the ability to probe molecules whose dynamics do not work well with crystallization. With the recent advances in the area, there is much hope that the method can outperform established techniques in the very near future. 

Artificial Intelligence & Deep Learning

While not precisely a biophysical method, the entire field of biophysics and structural biology is experiencing a revolution with the increasing adoption of artificial intelligence. At the start of 2022, Nature named protein structure prediction the method of the year. AI-fueled protein structure prediction has upended the world of structural biology, through platforms such as AlphaFold2 and RoseTTAfold. These platforms focus on providing the 3D structures of specific proteins, but variations on AlphaFold also provide predictions for multiprotein complexes, protein dynamics, ligand interactions and even RNA structure. These hold immense scope for turbocharging the progress of novel drug modalities such as small-molecule chimeras, antibody conjugates, RNA-based therapeutics, and others. With platforms such as these removing much of the laborious work in structure characterization, structural biologists are instead liberated to work on answering fundamental questions about the function and behaviour of the molecules they would be investigating. 

Artificial Intelligence and protein prediction also hold unique potential to accelerate the development of cryo-EM-derived methods. These include cryo-electron tomography and focused-ion beam scanning electron microscopy, which can visualize intact cells and characterize subcellular organization and localization. Although the images provided by cryo-ET methods may be of a lower resolution, combining these with data obtained from protein prediction can result in accurate characterizations of nearly atom-resolution models of protein complexes in their natural physiological contexts. 

Significance for Novel Drug Modalities

Emerging drug modalities across the life sciences have quite a few characteristics in common – and the majority of those come with an increased requirement for ever greater detail and accuracy in structural understanding. For example, antibody-based treatments require accurate prediction of binding sites and specificity, while antibody fragments require further understanding in investigating what membranes and barriers they are able to cross. The same is true for all peptide-based products.

Conjugated drug modalities have also been a rapidly growing field, including bispecific antibodies or small molecules and antibody-drug or oligonucleotide conjugates. These drug modalities do not merely require the traditional understanding of how each of their components behave in their targeted physiological contexts, but also off-site ones in their totality. In addition to that, they require competent ligand technology that can connect multiple components of the final product together, which retains stability until it reaches its intended destination. Even cytokine therapies are seeing conjugation technology being attached to them to increase their specificity – read more about the topic in our interview with Randi Isaacs.

The same is true for RNAi-based therapeutics, which are characterized by the need for sophisticated vehicles to maintain their stability until they reach their target – particularly when they are not conjugated. While the individual specifics of each emerging modality may differ, their common denominator is an increase in complexity – both in how the drug is delivered, but also in how the drug needs to be investigated for its full spectrum of effects throughout the body to improve its efficacy and safety profile.

Biophysics: An indispensable tool for the future

Our own growth in understanding has turned drug modalities that were previously unviable into some of the fastest-growing fields in the industry. One small example is how RNA interference technology had languished for the better part of the early 21st century, despite its boundless potential. Our own improvements in surveying the journey of drug candidates in the body, and ascertaining their role in their physiological contexts have proven vital in reviving interest across these fields, while also expediting progress in other fields – such as immunotherapies, targeted therapies and conjugated compounds. The advances in biophysics and structural biology directly correlate with this progress, and future developments on the shoulders of large strides in protein prediction and cryo-electron microscopy are bound to be no less exciting.

Nick Zoukas, Former Editor, PharmaFEATURES

Join Proventa International’s Drug Discovery Biology Strategy Meeting in Boston to hear the latest developments at the interface of drug discovery, biophysics and structural biology, as well as meet and listen to some of the brightest minds throughout the field.