Role of salt bridge dynamics in inter domain recognition of human impdh isoforms: An insight to inhibitor topology for isoform-ii

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 I_N—C₁ inter-domain of hIMPDH-I, I_N—C₂ of IMPDH-II and C₁—I_C of nhIMPDH-II are discriminative features among the isoforms. The I_N—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.