New research could significantly accelerate drug discovery

January 17, 2018, University of Maryland School of Medicine

Many drugs work by inhibiting protein enzymes associated with a particular disease. Unfortunately, the same drugs can inhibit protein enzymes unrelated to the disease, resulting in harmful side effects. One potential solution is to better identify structural features that determine a protein enzyme's function.

Now, a team headed by a computational biologist at the University of Maryland School of Medicine (UMSOM) has developed a suite of computer programs that cull through data on structure and genomic sequencing to identify the features that distinguish one enzyme from similar enzymes. This research has the potential to significantly accelerate drug discovery, allowing scientists to develop more effective drugs, more quickly.

"This new approach allows proteins to be analyzed at a much deeper, more specific level," says Andrew F. Neuwald, PhD, Professor of Biochemistry & Molecular Biology, a senior scientist at the Institute for Genome Sciences (IGS) at UMSOM, and the lead author of the paper describing the new method. "This method provides clues regarding sequence and structural features responsible for a 's specific biological function."

The paper was published this week in the journal eLife. Dr. Neuwald collaborated on the work with L. Aravind, PhD, and Stephen F. Altschul, PhD, two senior investigators at the National Center for Biotechnology Information at the National Institutes of Health.

In the paper, the investigators used this approach to identify the key features of various enzymes: N-acetyltransferases, P-loop GTPases, RNA helicases, synaptojanin-superfamily phosphatases and nucleases, and thymine/uracil DNA glycosylases. The results revealed striking and previously overlooked structural features likely associated with each protein's function. This has the potential to lead researchers to new ways of designing drugs that have fewer unintended, .

The two main programs are BPPS (Bayesian Partitioning with Pattern Selection), and SIPRIS (Structurally Interacting Pattern Residues' Inferred Significance). The programs and source code are freely available and require only a minimal knowledge of Linux, thereby making this approach widely accessible to other researchers. This approach will also be useful for protein engineering and for understanding the molecular basis of many human diseases.

The three researchers each brought something different to the work. Dr. Neuwald, who has worked on protein analysis for years, has a varied background, with experience in , computer science and Bayesian statistics. Dr. Aravind is a well-known computational biologist with a broad knowledge of and function. Dr. Altschul, whose formal training is in mathematics, was the first author on two landmark publications describing the popular sequence database search programs BLAST and PSI-BLAST.

Explore further: Researchers develop new way to decode large amounts of biological data

More information: Andrew F Neuwald et al. Inferring joint sequence-structural determinants of protein functional specificity, eLife (2018). DOI: 10.7554/eLife.29880

Related Stories

Researchers report first 3-D structure of DHHC enzymes

January 11, 2018

The first three-dimensional structure of DHHC proteins—enzymes involved in many cellular processes, including cancer—explains how they function and may offer a blueprint for designing therapeutic drugs. Researchers have ...

Fundamental discovery casts enzymes in new light

November 8, 2011

Just as a breeze causes leaves, branches and ultimately the tree to move, enzymes moving at the molecular level perform hundreds of chemical processes that have a ripple effect necessary for life. Protein complexes are often ...

Researchers use new approach to predict protein function

July 11, 2007

In a paper published online this month in the journal Nature Chemical Biology, researchers report that they have developed a way to determine the function of some of the hundreds of thousands of proteins for which amino acid ...

Recommended for you

Honey, I shrunk the cell culture

October 23, 2018

From "Fantastic Voyage" to "Despicable Me," shrink rays have been a science-fiction staple on screen. Now chemists at The University of Texas at Austin have developed a real shrink ray that can change the size and shape of ...

Inexpensive chip-based device may transform spectrometry

October 23, 2018

Spectrometers—devices that distinguish different wavelengths of light and are used to determine the chemical composition of everything from laboratory materials to distant stars—are large devices with six-figure price ...

Cheminformatics approaches to creating new hair dyes

October 23, 2018

Finding the next generation of safer hair dyes may be as simple as going to the library – in this case, NC State's Max Weaver Dye Library. The dye library, donated by the Eastman Chemical Company, contains nearly 100,000 ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.