Theoretical Studies On Dimethylarginine Dimethylaminohydrolase-1

Dimethylarginine dimethylaminehydrolase(DDAH) is a cytosolic protein including two isoforms DDAH-1 and DDAH-2, it can hydrolyze endogenous nitric oxide synthase(NOS) inhibitor Nω-methyl-L-arginine and Nω, Nω- dimeth- yl-L-arginine(ADMA) specifically to increase the NOS activity, it has an important signification for curing the disorders caused by the NOS. Lots of crystal structures of DDAH-1 and its complexes with inhibitors are analyzed, which enable us to understand the structure of DDAH-1 and the bonding mode and interaction with its inhibitors in the atom level. However, static conformation analysis is limite for the dynamic process of the conformation when studing the interaction between DDAH-1 and its inhibitors. In the this paper, the interaction and combination mode of DDAH-1 and its inhibitors N5-(1-iminobut-3-enyl)-L- ornithine(L-VNIO),N5-(1-iminopropyl)-L-ornithine(Me-L-NIO) and Nω-(2-me- thoxyethyl)-L-arginine(L-NMEA) were studied by using the methods of molecular docking and molecular dynamics simulations, therefore, the relationship between the structure and function of DDAH-1 can be well understood, and the more effective N5-(1-iminobut-3-phenyl)-L-ornithine(Ph-L- NIO) inhibitor is designed according the experimental results which will be a reference for designing the medicine treating the NOS dysfunction diseases.This paper mainly contains following aspects:1.3D structures of DDAH-1 have been given by X-ray and NMR experiment, and the 3D structures of DDAH-1 were optimized by using of Discover-3 program. The ligands such as L-VNIO,Me-L-NIO,L-NMEA and Ph-L-NIO were designed by using of Builder program, and all the primary geometry structures were optimized under the B3LYP/6-31G(d, p) level using the Gaussian03 program. 2.Form the literature of Frey, it can be found that the active pocket of DDAH-1 mainly consists of the following amino acid residues: Asp72,Phe75,Asp78,Arg97,Arg144,His172 and Asp268, theoretical approach is never needed to search in this paper. The molecular docking was used by Affinity program, comformations of the lowest energy were selected form the collecting optimal 10 conformations to be the investigated goal of dynamic simulation(L-DDAH-1,M-DDAH-1,N-DDAH-1 and P-DDAH-1).3.The complexes(L-DDAH-1 and N-DDAH-1) for dynamic simulation were used by Discover-3 program. The interaction and combination mode between DDAH-1 and its inhibitors(L-VNIO and L-NMEA) were studied, the result shows: the combination of L-VNIO with DDAH-1 is stronger than L-NMEA, which is consistent with the value of IC₅₀ in experiment obtained.4.The complexes (M-DDAH-1 and P-DDAH-1) for dynamic simulation were used by Discover-3 program. The interaction and combination mode between DDAH-1 and its inhibitors(L-VNIO,Me-L-NIO and Ph-L-NIO) were studied, the result shows: the combination of L-VNIO with DDAH-1 is stronger than Me-L-NIO, which is consistent with the value of IC₅₀ in experiment obtained, and the combination of Ph-L-NIO with DDAH-1 is the most effectively.