O1-3

Interaction analysis of AKR1C3-inhibitor complexes using
fragment molecular orbital method andmolecular dynamics simulation
Hikari Yoshimoto 1

2033310131k@kindai.ac.jp

12

Norihito Kawashita 2

nkawashita@life.kindai.ac.jp

Graduate School of Science and Engineering, Kindai University, 3-4-1 Kowakae,Higashiosaka-shi, Osaka,577-8502, Japan
Faculty of Science and Engineering, Kindai University, 3-4-1 Kowakae, Higashiosaka-shi,Osaka, 577-8502, Japan

Keywords: AKR1C3, Fragment Molecular Orbital Method, Molecular Dynamics Simulation
AKR1C3 belongs to the aldehyde-reductase (AKRs) family and has high-homology with AKR1C1,C2, and C4 [1]. Therefore, there is concern that side effects due to cross -inhibition may occur. InAKR1C3, it is expected that a more potent and selective inhibitor can be obtained by binding theinhibitor to the SP1 region consisting of Ser118, Asn167, Phe306, Phe311, and Tyr319 [2].
In this study, we performed interaction analysis of AKR1C3 inhibitor complexes and AKR1C2
inhibitor complexes by fragment molecular orbital (FMO) method and molecular dynamics (MDs)simulations to develop inhibitors with high selectivity for AKR1C3.
The crystal structures of AKR1C3 and AKR1C2 inhibitor complex which IC 50 have been known
in the literature [3-5] were downloaded from Protein Data Bank (PDB). Structural modifications
and optimizations were performed using MOE. We also prepared the complexes that was notregistered in the PDB by MOE Dock. 100 ns MD-simulations were performed using GROMACS for
these structures, and a total of 10 structures were acquired in each complex, one for every 10 ns .
FMO calculations were performed for the acquired structures and the inter -fragment interactionenergies (IFIE) and PIEDA between each residue and inhibitor were calculated. ABINIT-MP wasused as the FMO calculation, and MP2/6-31G* was used as the calculation level.
MD-simulations indicated that the interaction between SP1 in the ligand binding pocket and theinhibitor was weak in AKR1C2, and the inhibitor tended to approach Lys84 in many cases, so theinteraction between the SP1 residue and the inhibitor is important. PIEDA also suggest that thedispersion energy (DI) of Phe306, Phe311 of SP1 contribute to the selectivity.
This research was done in activities of the FMO drug design consortium (FMODD). For FMO
calculations, RIKEN R-CCS Fugaku and Oakforest-PACS at JCAHPC were used (hp210130 quota).
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