Fragment-Based Drug Discovery Using a Multidomain, Parallel MD-MM/PBSA Screening Protocol

Abstract

We have developed a rigorous computational screening protocol to identify novel fragment-like inhibitors of N5-CAIR mutase (PurE), a key enzyme involved in de novo purine synthesis that represents a novel target for the design of antibacterial agents. This computational screening protocol utilizes molecular docking, graphics processing unit (GPU)-accelerated molecular dynamics and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) free energy estimations to investigate the binding modes and energies of fragments in the active sites of PurE. PurE is a functional octamer comprised of identical subunits. The octameric structure, with its eight active sites, provided a distinct advantage in these studies because, for a given simulation length, we were able to place eight separate fragment compounds in the active sites to increase the throughput of the MM/PBSA analysis. To validate this protocol, we have screened an in-house fragment library consisting of 352 compounds. The theoretical results were then compared with the results of two experimental fragment screens, Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) binding analyses. In these validation studies, the protocol was able to effectively identify the competitive binders that had been independently identified by experimental testing, suggesting the potential utility of this method for the identification of novel fragments for future development as PurE inhibitors.

Comparison of radii sets, entropy, QM methods, and sampling on MM‐PBSA, MM‐GBSA, and QM/MM‐GBSA ligand binding energies of F. tularensis enoyl‐ACP reductase (FabI)

“…Although MM‐P(G)BSA methods have been used successfully in both virtual screening and lead optimization programs, it has been shown that the results are sensitive to atomic charges, simulation length, entropy calculations, and sampling protocols which can lead to dramatic differences in affinity predictions using the same study system . Studies have also suggested that prediction results of MM‐GBSA methods might be influenced by radii settings .…”

Fast Docking on Graphics Processing Units via Ray-Casting

“…Methods that require long serial trajectories, such as those built upon molecular dynamics [23], [24], require frequent CPU-GPU communication. This in turn leads to latency that limits the speedup achievable through GPU computing.…”

“…A variety of biomolecular modeling tasks have been adapted for GPU processing, from carrying out quantum calculations to calculating electrostatic surface potentials to stochastic modeling of chemical kinetics and molecular dynamics [17]–[22]. GPU computing has also been used to speed up certain other structure-based docking tools [23]–[29].…”

Discovery of novel bacterial elongation condensing enzyme inhibitors by virtual screening

“…2A). 15, 16 This analysis showed that His298, Phe392, Thr302, Phe390, Val270, Pro272, Thr300, Gly391 and His333 contribute to TLM binding.…”