Role of Salt Bridge Dynamics in Inter Domain Recognition of Human IMPDH Isoforms: An Insight to Inhibitor Topology for Isoform-II

Abstract

Inosine monophosphate dehydrogenase (IMPDH) enzyme involves in the biosynthesis pathway of guanosine nucleotide. Type II isoform of the enzyme is selectively upregulated in neoplastic fast replicating lymphocytes and CML cancer cells. The hIMPDH-II is an excellent target for antileukemic agent. The detailed investigation during MD-Simulation (15 ns) of three different unliganded structures (1B3O, 1JCN and 1JR1) have clearly explored the salt bridge mediated stabilization of inter or intra domain (catalytic domains IN, with res. Id. 28–111 and 233–504, whereas two CBS domains C1, C2 are 112–171 and 172–232) in IMPDH enzyme which are mostly inaccessible in their X-rays structures. The salt bridge interaction in IN—C1 inter-domain of hIMPDH-I, IN—C2 of IMPDH-II and C1—IC of nhIMPDH-II are discriminative features among the isoforms. The IN—C2 recognition in hIMPDH-II (1B3O) is missing in type-I isoform (1JCN). The salt bridge interaction D232—K238 at the surface of protein and the involvement of three conserved water molecules or the hydrophilic centers (WA232 OD1, WB232 OD2 and W238 NZ) to those acidic and basic residues seem to be unique in hIMPDH-II. The hydrophilic susceptibility, geometrical and electronic consequences of this salt bridge interaction could be useful to design the topology of specific inhibitor for hIMPDH-II which may not be effective for hIMPDH-I. Possibly, the aliphatic ligand containing carboxyl, amide or hydrophilic groups with flexible structure may be implicated for hIMPDH-II inhibitor design using the conserved water mimic drug design protocol.