Optimization of an in silico protocol to characterize membrane PAINS

Abstract

Membrane Pan-Assay INterference compoundS (PAINS) are a class of molecules that interact non-specifically with lipid bilayers and alter their physicochemical properties. An early identification of these compounds avoids chasing false leads and the needless waste of time and resources in drug discovery campaigns. In this work, we optimized an in silico protocol based on umbrella sampling (US)/MD simulations to discriminate between compounds with different membrane PAINS behavior. We showed that the method is quite sensitive to membrane thickness fluctuations, which was mitigated by changing the US-reference position to the P-atoms of the closest interacting monolayer. The computational efficiency was improved further by decreasing the number of umbrellas and adjusting their strength and position in our US scheme. The ISDM-calculated membrane permeability coefficients confirmed that resveratrol and curcumin have distinct membrane PAINS characteristics and indicate a misclassification of nothofagin in a previous work. Overall, we have presented here a promising in silico protocol which can be adopted as a future reference method to identify membrane PAINS.

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds

“…22 Topologies for the compounds were obtained using the automated topology builder server (ATB), 23−25 as previously described. 16,18 The force field parameters used for POPC were the ones included in GROMOS 54A7. 26,27 Long-range electrostatic interactions were computed with the particle mesh Ewald (PME) method 28,29 using a Fourier grid spacing of 0.12 nm and a cutoff of 0.9 nm for direct contributions.…”

“…Molecular dynamics simulations were performed using GROMACS 2018.6 − and the united-atom GROMOS 54A7 force field . Topologies for the compounds were obtained using the automated topology builder server (ATB), − as previously described. , The force field parameters used for POPC were the ones included in GROMOS 54A7. , …”

“… 22 Topologies for the compounds were obtained using the automated topology builder server (ATB), 23 − 25 as previously described. 16 , 18 The force field parameters used for POPC were the ones included in GROMOS 54A7. 26 , 27 …”

“…Ingólfsson and co-workers explored the membrane perturbation effects of several phytochemicals in membranes and mechanosensitive membrane proteins through a combination of gramicidin-based assays (experimental) and coarse-grained molecular dynamics (MD) simulations. The developed protocol, which relied on computationally demanding umbrella sampling (US) simulations, worked as the basis for several subsequent methodologies. − …”

“…The developed protocol, which relied on computationally demanding umbrella sampling (US) simulations, worked as the basis for several subsequent methodologies. 16 − 18 …”