Quantifying biogenic bias in screening libraries.

In lead discovery, libraries of 10(6) molecules are screened for biological activity. Given the over 10(60) drug-like molecules thought possible, such screens might never succeed. The fact that they do, even occasionally, implies a biased selection of library molecules. We have developed a method to quantify the bias in screening libraries toward biogenic molecules. With this approach, we consider what is missing from screening libraries and how they can be optimized

SENSAAS (SENsitive Surface As A Shape): utilizing open-source algorithms for 3D point cloud alignment of molecules

Open-source 3D data processing libraries originally developed for computer vision and pattern recognition are used to align and compare molecular shapes and sub-shapes. Here, a shape is represented by a set of points distributed on the van der Waals surface of molecules. Each point is colored by its closest atom, which itself belongs to a user defined class. The strength of this representation is that it allows for comparisons of point clouds of different kind of chemical entities: small molecules, peptides, proteins or cavities (the negative image of th

SuperMimic – Fitting peptide mimetics into protein structures

BACKGROUND: Various experimental techniques yield peptides that are biologically active but have unfavourable pharmacological properties. The design of structurally similar organic compounds, i.e. peptide mimetics, is a challenging field in medicinal chemistry. RESULTS: SuperMimic identifies compounds that mimic parts of a protein, or positions in proteins that are suitable for inserting mimetics. The application provides libraries that contain peptidomimetic building blocks on the one hand and protein structures on the other. The search for promising peptidomimetic linkers for a given peptide is based on the superposition of the peptide with several conformers of the mimetic. New synthetic elements or proteins can be imported and used for searching. CONCLUSION: We present a graphical user interface for finding peptide mimetics that can be inserted into a protein or for fitting small molecules into a protein. Using SuperMimic, promising locations in proteins for the insertion of mimetics can be found quickly and conveniently

Structure based drug design for the discovery of promising inhibitors of human Bcl-2 and Streptococcus dysgalactiae LytR proteins

Drug research has evolved significantly in the last decades toward the concept of the rational design of drugs. The capability to study molecular interactions at the atomic level and to rationalize this knowledge to construct and improve drug candidates provided the premises of structure-based drug design (SBDD). This approach allied to the computational methods available nowadays yields the opportunity to expedite the intricate process of drug discovery. In the present thesis, the SBDD approach was implemented to study promising candidate inhibitors of the human Bcl-2 and the Streptococcus dysgalactiae LytR proteins. Half of the cancers in humans are estimated to be related with overexpression of Bcl-2 protein. This macromolecule is responsible for the inhibition of the apoptotic process, which is pivotal for the elimination of abnormal cells. When Bcl-2 is overexpressed, these abnormal cells don’t respond to death stimuli, either endogenous or exogenous, such as chemotherapeutic, and become immortal. Promising 4H-chromene and indole derivatives were studied regarding their potential to inhibit Bcl-2. Molecular docking studies revealed sub-micromolar binding of the 4Hchromene activemethine and the indole derivatives in the binding groove essential for Bcl-2 biological function. Biophysical characterization did not demonstrate significant evidence of binding between Bcl-2 and the compounds under study, probably due to their small network of interactions with the binding pocket residues. The structure determination process of the proteinligand complexes achieved preliminary co-crystallization conditions that require further optimization. Numerous infectious diseases are associated to the bacterial biofilm phenotype, which consists of agglomerates of cells enclosed in a self-produced matrix. Biofilms confer bacteria improved resistance to the host’s innate immune system and to conventional antibiotics. LytR belongs to the LCP family of proteins, which are thought to be responsible for the attachment of anionic polymers to the peptidoglycan, protecting the Gram-positive bacteria from phagocytosis and lysis. Previous virtual screening studies yielded ellagic acid and fisetin has promising inhibitors of LytR, displaying anti-biofilm activity. Molecular docking revealed binding of these compounds in the hypothetical active site of LytR, with micromolar affinities, and specific interactions with crucial protein residues for catalysis. Biophysical techniques failed to provide evidence of protein-ligand interactions, although this may be related to the possible co-purification with a lipidic substrate, which has been reported before. Mass spectrometry or structural determination, through X-ray crystallography or NMR, should be pivotal to establish evidence of this molecule’s accommodation in the binding pocket