Research Highlights

Novel Concept of "Active Conformational States" Introduced into RCS


Lauded by Biomedical Research Community , the relaxed complex scheme (RCS) is a promising computational method for computer-aided drug discovery (CADD) that combines the advantages of docking algorithms with the dynamic structural information provided by molecular dynamics (MD) simulations. The relaxed complex scheme (RCS) addresses the receptor protein target flexibility using the molecular dynamics simulation technique. RCS was pioneered in a study by Schames et al. (2004), which aided in the development of raltegravir (brand name Isentress), a novel HIV drug targeting the viral integrase. Since then, a number of new studies have further validated the use of RCS for drug discovery in a number of other case studies (Amaro 2008). Undecaprenyl pyrophosphate synthase (UPPs) is a cis-prenyltransferase enzyme, which is required for cell wall biosynthesis in bacteria. UPPs is an attractive target for antimicrobial therapy. Molecular dynamics (MD) simulations indicate that UPPs is a highly flexible protein with mobile binding pockets in the active site. We recently published a study (Sinko et al. 2011) which introduced the novel concept of “active conformational states” into RCS through an elegant combination of experimental and computational experiments. We performed long molecular dynamics simulations and docking studies on UPPs to investigate its dynamic behavior and the influence of protein flexibility on the design of UPPs inhibitors. By carrying out docking studies with experimentally validated UPPs inhibitors using high- and low-populated conformational states extracted from the MD simulations, we demonstrated that structurally dissimilar compounds can bind preferentially to different and rarely sampled conformational states. By performing structural analyses on a newly obtained apo-UPPs crystal structure and other crystal structures previously published, the study shows that the changes observed during the MD simulation are very similar to those seen in the crystal structures obtained in the presence or absence of ligands. A ligand is a small molecule that will bind tightly to its target; they are commonly used in computational approaches to drug discovery. This is the first time that a rare, dramatically ‘expanded pocket’ state, key to drug design and verified by crystallography, has been extracted from a molecular dynamics simulation. This study has been cited by Faculty of 1000 (a post-publication peer review service which identifies and evaluates significant biomedical research articles) as a ‘Must Read’ (Verma 2011).


  1. Schames, J.R., et al., Discovery of a novel binding trench in HIV integrase. J Med Chem, 2004. 47(8): p. 1879-81.
  2. Amaro, R.E., R. Baron, and J.A. McCammon, An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J Comput Aided Mol Des, 2008. 22(9): p. 693-705.
  3. Sinko, W., et al., Applying molecular dynamics simulations to identify rarely sampled ligand-bound conformational states of undecaprenyl pyrophosphate synthase, an antibacterial target. Chem Biol Drug Des, 2011. 77(6): p. 412-20.
  4. Verma, C. Technical Advance, Novel Drug Target. 2011; Available from:

NBCR Researchers: J. Andrew McCammon (Core Lead - Computer Aided Drug Discovery), William Sinko, Cesar de Oliveira, Sarah Williams, Jacob Durrant, Eric Oldfield, (Collaborative Project Lead)


  • (A) Superposition of docked (colored by atom type) and co-crystallized pose (green) of BPH-629 into the 2E98 crystal structure.
  • (B) Docked poses of 29 BPH inhibitors into the 2E98 structure.
  • (C) Docked poses of 1i, 1j, 4a, 4g, 4j, 4l and 4m into the 2E98 structure. Ligand poses showed a very poor alignment with the substrate, FPP (shown in green).
  • (D) Docked poses of 1i, 1j, 4a, 4g, 4j, 4l and 4m into the fourth most populated MD-derived structure. All ligand poses showed a very good alignment with the substrate, FPP (shown in green).