It’s molecular!

Fujitsu develops molecular simulation technology to effectively create new drug candidates

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TOKYO & KAWASAKI, Japan—In early May, Fujitsu Laboratories Ltd. and Fujitsu Limited announced the development of molecular simulation technology for drug discovery that can accurately estimate binding affinity, which represents the degree to which target proteins bind to chemical substances that could become candidate drugs.
Fujitsu Laboratories has developed molecular simulation technology that estimates the degree of torsion in a chemical substance, which is directly connected to the predicted binding affinity. The new technology takes into account not only the bonding location where the torsion will occur, but also the impact of neighboring atoms. Fujitsu Laboratories evaluated this technology for 190 types of chemical substances, comparing the results with correct results arrived at from first principles calculation, and then evaluating the error rate. Researchers were able to confirm that the error rate in the estimate of the degree of torsion was, on average, one-tenth that of previous technology.
The use of this new technology in IT-based drug discovery, with its ability to accurately estimate the binding affinity of targeted proteins and chemical substances, offers the potential for groundbreaking new drug discovery efforts that could not be achieved with previous approaches. Fujitsu Laboratories plans to include this technology in a new IT-based drug discovery service offered by Fujitsu Limited.
The discovery of new drugs requires significant expenses and timeframes that can be measured in decades, leading to a global search for new methods of discovering drugs. One of the methods that has received considerable interest is IT-based drug discovery. This method has become a focal point for expectations as a groundbreaking technology for the creation of new drugs because unlike previous methods, this approach makes it possible to virtually design chemical substances and estimate their effects.
Fujitsu Laboratories has been developing molecular simulation technology for more than 10 years. Now, using the knowledge it obtained through previous efforts, Fujitsu Laboratories has developed a molecular simulation technology that can estimate the dihedral angle parameter by taking into consideration the impact of atoms near the bond.
“In the process of researching these molecular simulation technologies, we encountered a problem of low estimation accuracy for certain critical parameters,” Dr. Azuma Matsuura of Fujitsu Laboratories tells DDNews. “Specifically, we carefully investigated why the accuracy is so low in some cases for estimations of the parameter of the dihedral angle, which is necessary to calculate the degree of torsion at the bond between atoms in a molecule—accurately estimating the degree of torsion is directly connected to the ability to accurately predict binding affinity between target proteins that cause diseases and chemical substances that could be drug candidates. In effect, we arrived at the conclusion that depending on the molecular structure, the impact of atoms adjacent to the dihedral angle bond greatly influences the accuracy of estimations. This discovery sparked the development of this technology.”
Existing technology estimates the dihedral angle parameter based on a total of four atoms: the two atoms in the relevant bond, and the other atoms each of those atoms is bonded to. Depending on the structure of the molecule, however, there are cases where atoms beyond those four could have a significant impact, and in those cases, the margin of error of the estimation could be quite large.
With the new technology, Fujitsu Laboratories has created a database of estimation formulas for partial structure patterns where the impact of atoms farther away from the bond site could be significant, as well as for the degree of torsion of chemical substances that would be expected in that case. “Torsion is described as the most important parameter linked to the ‘binding affinity’ of a given substance. The binding affinity represents how well proteins that cause diseases bind to substances that could become candidate drugs. Previous methods have not offered accurate predictions of torsion, meaning that until now, the overall estimation of binding affinity has been relatively poor,” Matsuura notes.
“The new technology offers greater insight into the torsion of a substance, and hence offers better estimations of binding affinity of any given substance and its appropriateness as a new drug candidate,” Matsuura continues. “Using the relevant estimation formula to find the degree of torsion in the case of molecules corresponding to the database for partial structures, it has become possible to make highly accurate estimations for molecular torsion. Fujitsu Laboratories integrated this technology into the software it developed for generating sophisticated parameters for the forces between atoms.” When Fujitsu Laboratories integrated this technology into their FF-FOM software, it was able to confirm that the results conformed to accurate computations.
According to Matsuura, “This simulation technology enables us to more accurately predict the binding affinity of a chemical substances with disease causing proteins, which ... offers an indication of the substance’s potential effectiveness as a drug. This approach makes it possible to virtually design chemical substances and estimate their effects. Previous approaches to drug discovery until now required that chemical substances were repeatedly created and tested in a process of trial and error.
“Now, this approach may change as a diverse variety of substances that until now had not been assessed can be tested virtually with improved speed and accuracy, and these results can be accumulated and filtered for production and for conducting experiments. With the adoption of this technology, the instances in which IT will be used in drug discovery will likely increase, and we anticipate this will lead to the creation of groundbreaking new drugs that would not have been possible based on previous knowledge alone.”
Fujitsu Laboratories plans to include this technology in an IT-based drug discovery-related service that Fujitsu Limited plans to offer in the future. “Fujitsu envisions an HPC (high-performance computing) cloud computing service in the near future for delivering this technology. We will begin offering it from this fiscal year, and incrementally expand it. We plan to fully initiate the service by 2020,” concludes Matsuura.

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