Applying Molecular Dynamics Simulations to Identify Rarely Sampled Ligand‐bound Conformational States of Undecaprenyl Pyrophosphate Synthase, an Antibacterial Target

Abstract

Undecaprenyl pyrophosphate synthase is a cis-prenyltransferase enzyme, which is required for cell wall biosynthesis in bacteria. Undecaprenyl pyrophosphate synthase is an attractive target for antimicrobial therapy. We performed long molecular dynamics simulations and docking studies on undecaprenyl pyrophosphate synthase to investigate its dynamic behavior and the influence of protein flexibility on the design of undecaprenyl pyrophosphate synthase inhibitors. We also describe the first X-ray crystallographic structure of Escherichia coli apo-undecaprenyl pyrophosphate synthase. The molecular dynamics simulations indicate that undecaprenyl pyrophosphate synthase is a highly flexible protein, with mobile binding pockets in the active site. By carrying out docking studies with experimentally validated undecaprenyl pyrophosphate synthase inhibitors using high- and low-populated conformational states extracted from the molecular dynamics simulations, we show that structurally dissimilar compounds can bind preferentially to different and rarely sampled conformational states. By performing structural analyses on the newly obtained apo-undecaprenyl pyrophosphate synthase and other crystal structures previously published, we show that the changes observed during the molecular dynamics simulation are very similar to those seen in the crystal structures obtained in the presence or absence of ligands. We believe that this is the first time that a rare ‘expanded pocket’ state, key to drug design and verified by crystallography, has been extracted from a molecular dynamics simulation.

Dynamics of Plasmodium falciparum enoyl‐ACP reductase and implications on drug discovery

“…Picking conformations based on pocket volume may be an interesting approach to structure-based drug discovery, as has been previously shown by demonstrating better correlation between ligand binding affinities and docking scores for certain wide open pockets. 19 In summary, these results suggest that the protein adapts rapidly to accommodate different ligands. We thus speculate that accounting for receptor flexibility is crucial in drug-discovery studies focusing on PfENR.…”

“…In at least one example, this approach has yielded better structures for virtual screening than a simple cluster analysis. 19 Second, the dynamics of the ligand inside the binding pocket suggest several stabilizing interactions in addition to the ones known from crystallography. Designing drugs that exploit these additional, critical interactions will certainly be the target of future drug-discovery efforts.…”

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“…Systematic molecular modeling based on crystallographic studies enabled the definition of structural requirements for its inhibitors [183].…”

Resistance-resistant antibiotics

“…The MD result on UPPS[40] is shown in Figure 4A and indicates that for most of the time the active site is “closed” (volume V~400 Å 3 ) but at ~12 nsec it opens up to V~900Å 3 . The frequency of occurrence of a given pocket volume is shown in Figure 4B, with the largest MD pocket having a volume very similar to that seen in an inhibitor-bound structure (PDB ID code 2E98) containing 4 inhibitor molecules[41].…”