Decaprenyl pyrophosphate synthase (DPPS) is an isoprenoid polymerase synthesizing decaprenyl phosphate, a key component of Mycobacterium tuberculosis cell wall biosynthesis. As an attractive drug target against tuberculosis, we have performed molecular dynamics (MD) simulations on DPPS free and in complex with various ligands to investigate its dynamic behavior. Binding pocket volume calculations on the MD trajectories identified several transitions between open and closed states, revealing the structural plasticity of DPPS. To efficiently incorporate protein flexibility into our structure-based drug-discovery protocols, we carried out clustering analysis to select dominant conformational states of DPPS. We have identified receptor conformers with the best predictive power through virtual screening with active leads on clusters. Computational solvent mapping suggests potential allosteric ligand binding sites which may lead to the development of allosteric inhibitors. By coupling structure-based drug design with MD simulations, our work highlights the importance of accounting for protein flexibility in computer-aided drug discovery.

Exploring the conformational landscape of decaprenyl pyrophosphate synthase, a promising drug target against tuberculosis

245th National Meeting (2013)

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