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. 2011 Jan;79(1):42–50. doi: 10.1124/mol.110.066928

Fig. 5.

Fig. 5.

Addition of negative surface electrostatic potential through an ether linkage increases ROMK inhibitor potency. Two primary screening hits, VU590 (A) and BNBI (B), share the common substructure of flanking nitrophenyl groups linked by alkyl chains of different length and composition. Visualization of the distribution of electrostatic properties was achieved by displaying atom-centered point charges from the Merck Molecular Mechanics Forcefield (MMFF94) on a Connolly surface of each molecule (A–C). Atomic charge values are indicated by color ramp ranges from negative (red) to positive electrostatic potential (blue). When VU590 is flexibly aligned with BNBI (see Materials and Methods) and displayed in a similar conformation, localization of negative electrostatic potential in the middle portion of the molecule is observed. This is consistent with the rationale used to generate increased potency in VU591 (C) and suggests that the negative electrostatic potential of the ether linker contributes to the increased potency of VU591 toward ROMK. Right, conformational ensembles generated by SurflexSim (SybylX 1.1; Tripos) from the 10 top-scoring aligned conformers of VU590 (D), BNBI (E), and VU591 (F). The surface of the best-scoring, most similar alignment (gray Connolly surface) highlights increased flexibility within and flanking the VU590 macrocyclic linker relative to the bicyclic rings and propyl/ether linker of BNBI/VU591 that is consistent with enhanced ROMK selectivity observed experimentally with VU591 versus VU590.