SuperLigands – a database of ligand structures derived from the Protein Data Bank

BACKGROUND: Currently, the PDB contains approximately 29,000 protein structures comprising over 70,000 experimentally determined three-dimensional structures of over 5,000 different low molecular weight compounds. Information about these PDB ligands can be very helpful in the field of molecular modelling and prediction, particularly for the prediction of protein binding sites and function. DESCRIPTION: Here we present an Internet accessible database delivering PDB ligands in the MDL Mol file format which, in contrast to the PDB format, includes information about bond types. Structural similarity of the compounds can be detected by calculation of Tanimoto coefficients and by three-dimensional superposition. Topological similarity of PDB ligands to known drugs can be assessed via Tanimoto coefficients. CONCLUSION: SuperLigands supplements the set of existing resources of information about small molecules bound to PDB structures. Allowing for three-dimensional comparison of the compounds as a novel feature, this database represents a valuable means of analysis and prediction in the field of biological and medical research

A Conceptual Mathematical Model of the Dynamic Self-Organisation of Distinct Cellular Organelles

Formation, degradation and renewal of cellular organelles is a dynamic process based on permanent budding, fusion and inter-organelle traffic of vesicles. These processes include many regulatory proteins such as SNAREs, Rabs and coats. Given this complex machinery, a controversially debated issue is the definition of a minimal set of generic mechanisms necessary to enable the self-organization of organelles differing in number, size and chemical composition. We present a conceptual mathematical model of dynamic organelle formation based on interacting vesicles which carry different types of fusogenic proteins (FP) playing the role of characteristic marker proteins. Our simulations (ODEs) show that a de novo formation of non-identical organelles, each accumulating a different type of FP, requires a certain degree of disproportionation of FPs during budding. More importantly however, the fusion kinetics must indispensably exhibit positive cooperativity among these FPs, particularly for the formation of larger organelles. We compared different types of cooperativity: sequential alignment of corresponding FPs on opposite vesicle/organelles during fusion and pre-formation of FP-aggregates (equivalent, e.g., to SNARE clusters) prior to fusion described by Hill kinetics. This showed that the average organelle size in the system is much more sensitive to the disproportionation strength of FPs during budding if the vesicular transport system gets along with a fusion mechanism based on sequential alignments of FPs. Therefore, pre-formation of FP aggregates within the membranes prior to fusion introduce robustness with respect to organelle size. Our findings provide a plausible explanation for the evolution of a relatively large number of molecules to confer specificity on the fusion machinery compared to the relatively small number involved in the budding process. Moreover, we could speculate that a specific cooperativity which may be described by Hill kinetics (aggregates or Rab/SNARE complex formation) is suitable if maturation/identity switching of organelles play a role (bistability)

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

PROMISCUOUS 2.0: a resource for drug-repositioning

The development of new drugs for diseases is a time-consuming, costly and risky process. In recent years, many drugs could be approved for other indications. This repurposing process allows to effectively reduce development costs, time and, ultimately, save patients' lives. During the ongoing COVID-19 pandemic, drug repositioning has gained widespread attention as a fast opportunity to find potential treatments against the newly emerging disease. In order to expand this field to researchers with varying levels of experience, we made an effort to open it to all users (meaning novices as well as experts in cheminformatics) by significantly improving the entry-level user experience. The browsing functionality can be used as a global entry point to collect further information with regards to small molecules (∼1 million), side-effects ∼110 000) or drug-target interactions (∼3 million). The drug-repositioning tab for small molecules will also suggest possible drug-repositioning opportunities to the user by using structural similarity measurements for small molecules using two different approaches. Additionally, using information from the Promiscuous 2.0 Database, lists of candidate drugs for given indications were precomputed, including a section dedicated to potential treatments for COVID-19. All the information is interconnected by a dynamic network-based visualization to identify new indications for available compounds. Promiscuous 2.0 is unique in its functionality and is publicly available at http://bioinformatics.charite.de/promiscuous2

Coalescent angiogenesis—evidence for a novel concept of vascular network maturation

Angiogenesis describes the formation of new blood vessels from pre-existing vascular structures. While the most studied mode of angiogenesis is vascular sprouting, specific conditions or organs favor intussusception, i.e., the division or splitting of an existing vessel, as preferential mode of new vessel formation. In the present study, sustained (33-h) intravital microscopy of the vasculature in the chick chorioallantoic membrane (CAM) led to the hypothesis of a novel non-sprouting mode for vessel generation, which we termed "coalescent angiogenesis." In this process, preferential flow pathways evolve from isotropic capillary meshes enclosing tissue islands. These preferential flow pathways progressively enlarge by coalescence of capillaries and elimination of internal tissue pillars, in a process that is the reverse of intussusception. Concomitantly, less perfused segments regress. In this way, an initially mesh-like capillary network is remodeled into a tree structure, while conserving vascular wall components and maintaining blood flow. Coalescent angiogenesis, thus, describes the remodeling of an initial, hemodynamically inefficient mesh structure, into a hierarchical tree structure that provides efficient convective transport, allowing for the rapid expansion of the vasculature with maintained blood supply and function during development

Representation of target-bound drugs by computed conformers: implications for conformational libraries

BACKGROUND: The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. RESULTS: Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space. A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. CONCLUSION: Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site [1]. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available

Dictionary of Interfaces in Proteins (DIP). Data Bank of Complementary Molecular Surface Patches

From a historical point of view, molecular biology encompasses a period of data collection Abbreviations used: SSE, secondary structural element; MSP, molecular surface patch; ID, identi®er