Computational combat

Researchers combine molecular, quantum mechanics to screen for HIV compounds

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ODENSE, Denmark—The HIV virus remains a difficult one to treat due to its ability to constantly mutate and to protect vulnerable binding sites. In light of this tendency, drugs that have proven effective in the past can lose their potency, leading to a constant need for new drugs targeting new facets of the virus. Given the complexity of the virus, however, identifying compounds with the potential to target it effectively is a time-consuming process—one that researchers from the University of Southern Denmark have been able to speed up through a new screening model.
The researchers in question included postdoc Vasanthanathan Poongavanam, from the Department of Physics, Chemistry and Pharmacy at the University of Southern Denmark, and Jacob Kongsted, an associate professor in the same department.
“HIV is a retrovirus that contains enzymes which make it able to copy itself with the help of host genetic material and thus reproduce,” Poongavanam explains. “If you can block these enzymes’ ability to replicate itself, the virus cannot reproduce.”
The researchers’ new method is detailed in a pair of papers: “Binding free energy based structural dynamics analysis of HIV-1 RT RNase H-inhibitor complexes,” which appeared in Integrative Biology, and “Inhibitor Ranking through QM Based Chelation Calculations for Virtual Screening of HIV-1 RNase H Inhibition,” which appeared in Plos One. Among the findings resulting from their work, the former paper, as noted in the abstract, “describes in detail how the choice of initial ligand structures, e.g. protonation states, impacts the predicted ranking of the compounds,” while the latter reveals the tendency of “QM-based chelation calculations to significantly reduce the large number of false positives.”
So far, Poongavanam and Kongsted have used the new methods to screen half a million compounds, which turned up 25 compounds of interest. Those compounds were then tested in a conventional laboratory experiment, which in turn showed 14 of them were capable of inhibiting the HIV virus’ ability to reproduce. The promising candidates are now being explored by Italian researchers who will investigate them further at the University of Cagliari. Should advanced experiments bear out the compounds’ potential, they could be advanced as HIV drugs.
“Our approaches are not new, but we use a combination of existing approaches for this problem in a new way,” Poongavanam explains. “Methods that use molecular mechanics principles are often used to screen millions of chemical compounds in drug discovery because these methods are fast. But in our study, we used quantum mechanics in addition to molecular mechanics methods in order to put more effort in accuracy of the prediction.”
“These methods are very different in principle, but combining these methods solves many mysteries in understanding complex molecular recognition,” he continues. “Quantum mechanics is primarily used to study in detail how a compound binds to a protein at the atomic level; therefore, this method is very accurate, but slow. On the other hand, molecular mechanics-based methods are primarily used to understand large, complex structures at the molecular scale, and they are fast. In our study, we used a ‘hybrid’ in order to achieve more accuracy and speed. This approach is very powerful, and indeed became internationally recognized after the Nobel Prize (2013) was awarded to Prof. Martin Karplus, Prof. Michael Levitt and Prof. Arieh Warshel, who are considered pioneers in this growing field.”
Poongavanam adds that “These approaches could be applicable to other diseases, but it needs to be tested thoroughly, as we have only validated the models for this enzyme.” He expects to see approaches such as this, utilizing computer-based predictions and screening models, become more prevalent, noting that they are areas of interest for pharmaceutical and biotech companies.
Despite advances made in treatment and prevention awareness, 1.1 million people in the United States are living with HIV infection, according to The World Health Organization reports roughly 35.3 million people were infected worldwide as of 2012, with 1.6 million global deaths related to AIDS that year.

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