Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Conserved Water Mediated H-bonding Dynamics of Carboxamide group in NAD to Catalytic Asp 274 and His 93 in Human IMPDH
The Inosine Monophosphate Dehydrogenase ( hIMPDH ) -II of human is led to new interest as an excellent target for the design of isoform specific anti leukemic agent (1, 2 ). The stereodynamics and recognition of mono and di nucleotide binding pockets ( 3 ) through one conserved water molecular center ( 4 ) and the participation of catalytic Arg 322 through a conserved water molecular triad ( 5 ) seem to be important concerning to water mimic drug design. Conserved water molecules are also played a significant role in conformational transition or flexibility of “ loop ” and “flap” regions in unliganded form of enzyme , and was also used for anti leukemic drug design (6). Involvement of Asp–Gly–Gly–Ile–Gln (S1: 364–368) and Gly–Ser–Leu ( S2: 387–389 ) sequences in the recognition of inhibitor CPR (6-Chloropurine Riboside 50-Monophosphate ) through conserved water molecules have also indicated the rationality for modified CPR ligand ( 7 ). Attempt has been employed to investigate the role of water molecules in the recognition of NAD or its structural analogs to conserved catalytic D 274 of hIMPDH , which may be useful for IMPDH inhibitor design.
Extensive MD-Simulation studies of solvated x-ray structures of hIMPDH ( 1B3O, 1NFB , 1NF7 and 1JCN ) and their complexes with NAD or its analogs have revealed the presence of conserved water mediated interaction of those ligand to carboxylate center of catalytic Asp 274 in the different isoforms of enzyme ( Figure1 ). In the unliganded IMPDH , one conserved water molecule ( W 1 ) forms H- bond to D 274 ( OD2 ) and H 93. However , during the complexation of NAD or its analogs with IMPDH , that W1 retains its position and two other water molecules ( W 2 and WC ) are also observed to form H-bond with the carboxyl group of Asp 274. Position of these three water molecules ( WC , W 1 and W2 ) are also be conserved during MD-simulation. All the conserved water molecules have stabilized through H- bonds and occupied the three corners of a distorted trigonal pyramid with carboxyl oxygen ( OD2 ) at apex (Figure 2). The water molecule WC interacts to carboxamide group of nucleotide or its analogs. The recognition geometry of carboxamide NN7 of NAD or analogs to carboxyl group of Asp 274 through conserved water ( WC ) mediated interaction and their stereochemical features may be used for IMPDH inhibitor design. Possibly , the chemical signals of cofactor binding region ( NAD or its structural analogs ) could be transmitted to remote part of protein ( Figure 3 ) through Base ( NAD NN7 ) ---- Water ( WC )----- Acid ( D 274 OD2 ) ---- Base ( H93 NE2 ) H-bonding interaction.
Hridoy Ranjan Bairagya1*
1Department of Chemistry, National Institute of Technology –Durgapur, W.B., 713 209 India
Figure 1: Presence of conserved water molecules ( W1 , W2 ,WC ) and water mediated recognition of NAD to D 274 and H93 in the MD-simulated structure of 1B3O ,1NFB ,1NF7 and 1JCN. *MYD( NAD analog inhibitor ): C2 mycophenolic adenine dinucleotide
Figure 2: The transition of unliganded IMPDH to NAD –bound IMPDH structure in human.*DN= Di-nucleotide Ligand (NAD / structural analogs)
Figure 3: Conserved water mediated H-bonding interaction and the chemical signaling ( Base --- Water --- Acid --- ) of the NAD binding region in hIMPDH