New computer modelling could boost drug discovery

Scientists from Queen's University Belfast have developed a computer-aided data tool that could improve treatment for a range of illnesses.

The computer modelling tool will predict novel sites of binding for potential drugs that are more selective, leading to more effective drug targeting, increasing therapeutic efficacy and reducing side effects.

The data tool or protocol will uncover a novel class of compounds - allosteric drugs in G protein-coupled receptors (GPCRs).

GPCRs are the largest membrane protein family that transduce a signal inside cells from hormones, neurotransmitters, and other endogenous molecules. As a result of their broad influence on human physiology, GPCRs are drug targets in many therapeutic areas such as inflammation, infertility, metabolic and neurological disorders, viral infections and cancer. Currently over a third of drugs act via GPCRs. Despite the substantial therapeutic success, the discovery of GPCR drugs is challenging due to promiscuous binding and subsequent side effects.

Recent studies point to the existence of other binding sites, called allosteric sites that drugs can bind to and provide several therapeutic benefits. However, the discovery of allosteric sites and drugs has been mostly serendipitous. Recent X-ray crystallography, that determines the atomic and molecular structure, and cryo-electron microscopy that offers 3D models of several GPCRs offer opportunities to develop computer-aided methodologies to search for allosteric sites.

The researchers developed a computer-aided protocol to map allosteric sites in GPCRs with a view to start rational search of allosteric drugs, presenting the opportunity for new solutions and therapies for a range of diseases.

Dr Irina Tikhonova from the School of Pharmacy at Queen’s University and senior author, explains: “We have developed a novel, cost-effective and rapid pipeline for the discovery of GPCRs allosteric sites, which overcomes the limitations of current computational protocols such as membrane distortion and non-specific binding.

"Our pipeline can identify allosteric sites in a short time, which makes it suitable for industry settings. As such, our pipeline is a feasible solution to initiate structure-based search of allosteric drugs for any membrane-bound drug targets that have an impact on cancer, inflammation, and CNS diseases."

This research published in ACS Central Science is a collaboration with Queen's University Belfast and Queen Mary University of London. It is supported by the European Union ’s Horizon 2020 research and innovation programme under the Marie-Sklodowska-Curie grants agreement and Biotechnology and Biological Science Research Council.

Antonella Ciancetta, Amandeep Kaur Gill, Tianyi Ding, Dmitry S Karlov, George Chalhoub, Peter J McCormick, Irina G Tikhonova.
Probe Confined Dynamic Mapping for G Protein-Coupled Receptor Allosteric Site Prediction.
ACS Cent. Sci. 2021. doi: 10.1021/acscentsci.1c00802

Most Popular Now

Pfizer to provide U.S. government with 10 million …

Pfizer Inc. (NYSE: PFE) today announced an agreement with the U.S. government to supply 10 million treatment courses of its investigational COVID-19 oral antiviral candid...

GSK and Vir Biotechnology announce United States g…

GlaxoSmithKline plc (LSE/NYSE: GSK) and Vir Biotechnology, Inc. (Nasdaq: VIR) announced US government contracts totalling approximately $1 billion[1] (USD) to purchase so...

Primary endpoint met in COMET-TAIL Phase III trial…

GlaxoSmithKline plc (LSE/NYSE: GSK) and Vir Biotechnology, Inc. (Vir) (Nasdaq: VIR) announced headline data from the randomised, multi-centre, open-label COMET-TAIL Phase...

Two billion doses of AstraZeneca’s COVID-19 vaccin…

AstraZeneca and its partners have released for supply two billion doses of their COVID-19 vaccine to more than 170 countries across every continent on the planet in the l...

Merck and Ridgeback's molnupiravir, an oral COVID-…

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics announced that the United Kingdom Medicines and Healthcare products Re...

Johnson & Johnson COVID-19 vaccine named one o…

The editors of Time announced that the Johnson & Johnson COVID-19 vaccine has been selected as one of Time's Best Inventions of 2021. The vaccine, for which Johnson & ...

New target for COVID-19 vaccines identified

Next generation vaccines for COVID-19 should aim to induce an immune response against 'replication proteins', essential for the very earliest stages of the viral cycle, c...

Repurposing a familiar drug for COVID-19

For the past year and a half, the COVID-19 pandemic has continued to engulf the globe, fueled in part by novel variants and the uneven distribution of vaccines. Every day...

Safety concerns raised for neuroblastoma candidate…

St. Jude Children's Research Hospital scientists looking for drugs to improve survival of children with high-risk neuroblastoma found a promising candidate in CX-5461. Th...

Pfizer and BioNTech receive expanded U.S. FDA emer…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that the U.S. Food and Drug Administration (FDA) has expanded the emergency use authorization (EUA) of a ...

'Dancing molecules' successfully repair severe spi…

Northwestern University researchers have developed a new injectable therapy that harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal ...

A target for potential cancer drugs may, in fact, …

In recent years, much scientific effort and funding has focused on developing drugs that target an enzyme with the unwieldy name of Src homology 2-containing protein tyro...