New research could significantly accelerate drug discovery

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 protein'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, harmful side effects.

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 molecular biology, computer science and Bayesian statistics. Dr. Aravind is a well-known computational biologist with a broad knowledge of protein structure 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.

Neuwald AF, Aravind L, Altschul SF.
Inferring joint sequence-structural determinants of protein functional specificity.
Elife. 2018 Jan 16;7. pii: e29880. doi: 10.7554/eLife.29880.

Most Popular Now

Therapy using dual immune system cells effectively…

A newly developed immunotherapy that simultaneously uses modified immune-fighting cells to home in on and attack two antigens, or foreign substances, on cancer cells was ...

Cleveland Clinic study suggests steroid nasal spra…

A recent Cleveland Clinic study found that patients who regularly use steroid nasal sprays are less likely to develop severe COVID-19-related disease, including a 20 to 2...

How to develop new drugs based on merged datasets

Polymorphs are molecules that have different molecular packing arrangements despite identical chemical compositions. In a recent paper, researchers at GlaxoSmithKline (GS...

New drug combination effective against SARS-CoV-2 …

More countries with greater resources are opening up for a more normal life. But COVID-19 and the SARS-CoV-2 virus are still a significant threat in large parts of the wo...

Sanofi to focus its COVID-19 development efforts o…

Recent positive interim results of Sanofi's mRNA-based COVID-19 vaccine candidate Phase 1/2 study confirm the company's platform robust capabilities and strategy in mRNA...

Discovery of mechanics of drug targets for COVID-1…

A team of international researchers, including McGill Professor Stéphane Laporte, have discovered the working mechanism of potential drug targets for various diseases suc...

Phase II/III trial shows Ronapreve™ (casirivimab a…

Roche (SIX: RO, ROG; OTCQX: RHHBY) today confirmed positive data from the phase II/III 2066 study, investigating Ronapreve™ (casirivimab and imdevimab) in patients hospit...

Pfizer and BioNTech receive first U.S. FDA Emergen…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that the U.S. Food and Drug Administration (FDA) has authorized for emergency use a booster dose of the P...

AZD7442 request for Emergency Use Authorization fo…

AstraZeneca has submitted a request to the US Food and Drug Administration (FDA) for an Emergency Use Authorization (EUA) for AZD7442, its long-acting antibody (LAAB) com...

Pfizer and BioNTech receive CHMP positive opinion …

Pfizer Inc. (NYSE: PFE, "Pfizer") and BioNTech SE (Nasdaq: BNTX, "BioNTech") today announced that the Committee for Medicinal Products for Human Use (CHMP) of the Europea...

Boehringer Ingelheim acquires Abexxa Biologics to …

Boehringer Ingelheim announced the acquisition of Abexxa Biologics Inc., a biopharmaceutical company taking a new approach in the fields of immuno-oncology and oncology r...

GSK welcomes WHO recommendation for broad roll-out…

GlaxoSmithKline (GSK) plc welcomes and applauds the WHO recommendation for the broader deployment of GSK's RTS,S malaria vaccine to reduce childhood illness and deaths fr...