Comparative Molecular Dynamics Simulation of Aggregating and Non-Aggregating Inhibitor Solutions: Understanding the Molecular Basis of Promiscuity.

The presence of false positives in enzyme inhibition assays is a common problem in early drug discovery, especially for compounds that form colloid aggregates in solution. The molecular basis of these aggregates could not be thoroughly explored because of their transient stability. In this study we conducted comparative molecular dynamics (MD) simulations of miconazole, a strong aggregator, and fluconazole, a known non-aggregator. Interestingly, miconazole displays full aggregation within only 50 ns, whilst fluconazole shows no aggregation over the 500 ns simulation. The simulations indicate that the center of the aggregate is densely packed by the hydrophobic groups of miconazole, whereas polar and nonpolar groups comprise the surface to form a micelle-like colloid. The amphiphilic moment and planar nature of the miconazole structure appear to promote its aggregating behavior. The simulations also predict rapid aggregate formation for a second known promiscuous inhibitor, nicardipine. Thus, MD appears to be a useful tool to characterize aggregate-prone inhibitors at molecular-level detail and has the potential to provide useful information for drug discovery and formulation design.