Comparative Molecular Dynamics Simulation of Aggregating and Non-Aggregating Inhibitor Solutions: Understanding the Molecular Basis of Promiscuity
Authors: Richard A Bryce
Mohammad A Ghattas
Waleed A Zalloum
Noor Atatreh
Sara Al Rawashdah
Journal: ChemMedChem (2018)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: aggregators; colloids; micelles; molecular dynamics; promiscuous inhibitors.
Affiliations: College of Pharmacy, Al Ain University of Science and Technology, Al Ain, 64141, UAE., Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Oxford Road, Manchester, M13 9PL, UK., College of Pharmacy; Al Ain University of Science and Technology; Al Ain 64141 UAE, Faculty of Health Sciences, American University of Madaba, Amman, Jordan.

Abstract:  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. 

Retracted: No

PubPeer comments:
 The authors state that:  Both miconazole and fluconazole systems were created to mimic the experimental assay conditions, i.e., dissolution in DMSO and water with a given salt concentration (Tableu2005S1, Supporting Information) Taking a look at Table S1 of Supporting Information, we see the following:  Model building was guided by the aggregation assay conditions used by the Shoichet group where they identified miconazole as an aggregator and fluconazole as a non-aggregator using dynamic light scattering.[5] The assay system involved dissolving the compound of interest in DMSO and then put it an aqueous solution. The final assay solution had a drug concentration of 10 mM with 5% (v v) DMSO concentration and a salt concentration of 50 mM. The experimental conditions were mimicked by adding 11 molecules of solute molecules (~ 14 mM) then solvating it by DMSO (to roughly reach 5% v v) and then again solvating it by TIP3P water in an octahedron box (Table S1) It appears the authors attempted to mimic the experimental conditions used in Reference 5, which is the following paper: https: pubs.acs.org doi 10.1021 jm030191r In the Methods section of this paper, we read the following under  Dynamic Light Scattering , which describes the relevant concentrations used to test aggregation:  Drugs were dissolved to 10 or 50 mM in DMSO or 50 mM KPi buffer, and diluted with filtered 5 or 50 mM KPi. This gives the impression that the drugs were indeed prepared at 10 mM concentration first, but then they were diluted further using a KPi solution. Moreover, Table 2 of this reference lists the concentrations used for DLS measurements for miconazole and fluconazole (the two chemicals tested for aggregation in MD simulations here), which are 20 and 1000 micromolars, respectively. Therefore, the concentrations used in this MD simulation study does not appear to match those used in the reference used to determine them. This may have been caused by a misinterpretation of the assay conditions used in the reference paper given above. ,