MLP Tools: a PyMOL plugin for using the molecular lipophilicity potential in computer-aided drug design.

The molecular lipophilicity potential (MLP) is a well-established method to calculate and visualize lipophilicity on molecules. We are here introducing a new computational tool named MLP Tools, written in the programming language Python, and conceived as a free plugin for the popular open source molecular viewer PyMOL. The plugin is divided into several sub-programs which allow the visualization of the MLP on molecular surfaces, as well as in three-dimensional space in order to analyze lipophilic properties of binding pockets. The sub-program Log MLP also implements the virtual log P which allows the prediction of the octanol/water partition coefficients on multiple three-dimensional conformations of the same molecule. An implementation on the recently introduced MLP GOLD procedure, improving the GOLD docking performance in hydrophobic pockets, is also part of the plugin. In this article, all functions of the MLP Tools will be described through a few chosen examples.

Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing.

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a "computer-aided drug repurposing" approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators.

Limits of rapid log P determination methods for highly lipophilic and flexible compounds.

Lipophilicity is of crucial importance in many fields including pharmaceutical, environmental, cosmetic and food industries. Whereas different experimental strategies have been developed for rapid lipophilicity determination of new chemical entities, log P determination of highly lipophilic compounds is always challenging. In this study, three published chromatographic methods have been compared on a series of phenylalkanoic acids including the pro-perfume HaloscentD (HD-C12). Different log P values were obtained depending on the chromatographic method used for log P estimation. Molecular modelling suggested that log P variations may be due to the chromatographic conditions applied (isocratic or gradient mode, ratio methanol/water in the mobile phase), responsible of specific conformations of the molecule in solution. Thus, for flexible compounds, published methods have to be used with caution and considered as a good tool to estimate a log P range, depending on the molecular conformational state.

Modulation of toll-like receptor 4. Insights from x-ray crystallography and molecular modeling.

Toll-like receptors (TLRs) are a family of proteins with a key role in the innate immune system. They are specialized in the recognition of molecular patterns present in microbial components, through mechanisms not yet unraveled at atomic level. Improvement in the understanding of the molecular mechanisms that drive TLR signaling is of paramount importance to grasp key aspects of immunity, potentially leading to the design of new molecules able to modulate their functions. Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of gramnegative bacteria, activating the immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer, and rheumatoid arthritis. Reported X-ray crystal structures together with molecular modeling studies, not reviewed before in the literature, have recently contributed to the elucidation of key interactions at atomic level of the binding between the TLR4/MD-2 system and different TLR4/MD-2 ligands. The purpose of this review is to summarize these reported studies which may account for the SAR rationalization of natural/ synthetic agonist/antagonist TLR4 binders and may also guide further design of novel TLR4 modulators.