Comparative molecular dynamics simulation of aggregating and non-aggregating inhibitor solutions: understanding the molecular basis of promiscuity

Obtaining false positives in enzyme inhibition assays is a common problem in early drug discovery, especially those compounds which form colloid aggregates in solution. The molecular basis of these aggregates could not be thoroughly explored because of their transient stability. Here, we conduct comparative 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 centre of the aggregate is densely packed by the hydrophobic groups of miconazole whereas polar and non-polar groups comprise the surface, to form a micelle-like colloid. The amphiphilic moment and the planar nature of the miconazole structure appear to promote its aggregative behaviour. Simulation also predicts rapid aggregate formation for a second known promiscuous inhibitor, nicardipine. Thus, molecular dynamics appears a useful tool to characterize in molecular level detail aggregate-based inhibitors and has potential to provide useful input for drug discovery and formulation design.