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Computational Modeling Yields Potential Anti-Adenovirus Drugs

By BiotechDaily International staff writers
Posted on 15 Jul 2013
Image: Structures of the adenovirus proteinase in inactive form (turquoise) and activated (yellow) by binding of a cofactor (beige), in association with a promising inhibitor compound identified in this research (circular "ball and stick" molecule). In the inactive form, left, the inhibitor blocks the "pocket" into which the cofactor binds, thus preventing the enzyme from becoming active. In the fully activated enzyme, right, the inhibitor binds in the now-exposed protein-cleaving "active site," thus blocking the enzyme's protein-cleaving ability. The fact that this inhibitor works to disable the proteinase in two different ways at two different sites increases the chance that drugs based on this compound will be successful at fighting adenovirus infection. It also makes it less likely that adenovirus will develop resistance to such drugs (Photo courtesy of Brookhaven National Laboratory).
Image: Structures of the adenovirus proteinase in inactive form (turquoise) and activated (yellow) by binding of a cofactor (beige), in association with a promising inhibitor compound identified in this research (circular "ball and stick" molecule). In the inactive form, left, the inhibitor blocks the "pocket" into which the cofactor binds, thus preventing the enzyme from becoming active. In the fully activated enzyme, right, the inhibitor binds in the now-exposed protein-cleaving "active site," thus blocking the enzyme's protein-cleaving ability. The fact that this inhibitor works to disable the proteinase in two different ways at two different sites increases the chance that drugs based on this compound will be successful at fighting adenovirus infection. It also makes it less likely that adenovirus will develop resistance to such drugs (Photo courtesy of Brookhaven National Laboratory).
Advanced computational modeling was used to identify drug candidates capable of preventing replication of all serotypes of adenovirus.

Adenovirus infections most commonly cause diseases of the respiratory system. However, depending on the infecting serotype, they may also cause various other illnesses and presentations including gastroenteritis, conjunctivitis, cystitis, and rash illness. Respiratory diseases caused by adenovirus infection range from the common cold syndrome to pneumonia, croup, and bronchitis. Patients with compromised immune systems are especially susceptible to severe complications of adenovirus infection. As more than 50 distinct adenovirus serotypes have been identified, researchers doubt that it will be possible to develop a successful vaccine.

Instead, investigators at the Brookhaven National Laboratory (Upton, NY, USA) searched for compounds able to block the action of the adenovirus proteinase (AVP), an enzyme required by all serotypes during the process of replication within a host cell.

The investigators employed a process called "docking" to screen a library of more than 140,000 potential drugs. Docking—the computational simulation of a candidate ligand binding to a receptor—is a method that predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules. Docking is frequently used to predict the binding orientation of small molecule drug candidates to their protein targets in order to in turn predict the affinity and activity of the small molecule. Given the biological and pharmaceutical significance of molecular docking, considerable efforts have been directed towards improving the methods used to predict docking.

The AVP docking study, which was published in the May 24, 2013, online edition of the journal FEBS Letters, yielded 30 compounds able to block AVP. Further experiments showed that two of these compounds could inhibit AVP and prevent viral replication at clinically relevant concentrations. The two molecules are too large to be used as clinical drugs, so the next stage of the research effort will be to reduce their size during development of second-generation compounds based upon their binding segments.

"The adenovirus proteinase is an enzyme conserved throughout all strains of the virus that cleaves proteins during the assembly of new virus particles," said senior author Dr. Walter Mangel, a biologist at the Brookhaven National Laboratory. "Once those proteins are cleaved, the newly synthesized virus particle is infectious. If those proteins are not cleaved, then the infection is aborted. Thus, inhibitors of the adenovirus proteinase should be effective antiviral agents against all strains of adenovirus."

"This research is a great example of the potential for rational drug design," said Dr. Mangel. "Based on studies of the atomic-level structure of an enzyme that is essential for the maturation of adenovirus and how that enzyme becomes active—conducted at Brookhaven's National Synchrotron Light Source (NSLS)—we used computational modeling to search for compounds that might interfere with this enzyme and tested the best candidates in the lab. This work should pave the way for the development of effective drugs against all types of adenovirus infections."

Related Links:
Brookhaven National Laboratory


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