Iterative Stochastic Elimination (ISE) is a novel algorithm that was originally developed to solve extremely complex problems in protein structure and interactions, and has since been applied to diverse topics that share a few general “ingredients”: they are extremely complex, of combinatorial nature, may be presented as large sets of variables that can each have many alternative values, there is some interdependence of the variables on each other, and there is a scoring function that can evaluate each choice of the problems “configuration”; this is the set of single values of each of the variables that constitute its full presentation. Those are picked randomly in a large sample, the analysis of which allows decisions to be made for rejecting some values for each of the variables; thus resulting in a smaller set of potential combinations. This continues in iterations until the number of combinations allows all the remaining options to be computed exhaustively and to order them by their scores. ISE has been mainly applied to problems that are relevant to drug design and discovery. We demonstrate, among others, the use of ISE to determine the properties of molecular ensembles and to pick the best molecules (“focused libraries”) for hitting a specific target. Future ideas for using ISE are discussed, as well as mentioning its contributions to the construction of two start‐up companies.

Alzheimer’s disease (AD) is a complex and widespread condition, still not fully understood and with no cure yet. Amyloid beta (Aβ) peptide is suspected to be a major cause of AD, and therefore, simultaneously blocking its formation and aggregation by inhibition of the enzymes BACE-1 (β-secretase) and AChE (acetylcholinesterase) by a single inhibitor may be an effective therapeutic approach, as compared to blocking one of these targets or by combining two drugs, one for each of these targets. We used our ISE algorithm to model each of the AChE peripheral site inhibitors and BACE-1 inhibitors, on the basis of published data, and constructed classification models for each. Subsequently, we screened large molecular databases with both models. Top scored molecules were docked into AChE and BACE-1 crystal structures, and 36 Molecules with the best weighted scores (based on ISE indexes and docking results) were sent for inhibition studies on the two enzymes. Two of them inhibited both AChE (IC50 between 4–7 μM) and BACE-1 (IC50 between 50–65 μM). Two additional molecules inhibited only AChE, and another two molecules inhibited only BACE-1. Preliminary testing of inhibition by F681-0222 (molecule 2) on APPswe/PS1dE9 transgenic mice shows a reduction in brain tissue of soluble Aβ42.

Infectious diseases are still a major problem worldwide. This includes microbial infections, with a constant increase in resistance to the current anti-infectives employed. Toll-like receptors (TLRs) perform a fundamental role in pathogen recognition and activation of the innate immune response. Promising new approaches to combat infections and inflammatory diseases involve modulation of the host immune system via TLR4. TLR4 and its co-receptors MD2 and CD14 are required for immune response to fungal and bacterial infection by recognition of microbial cell wall components, making it a prime target for drug development. To evaluate the efficacy of anti-infective compounds early on, we have developed a series of human-based immune responsive infection models, including immune responsive 3D-skin infection models for modeling fungal infections. By using computational methods: pharmacophore modeling and molecular docking, we identified a set of 46 potential modulators of TLR4, which were screened in several tests systems of increasing complexity, including immune responsive 3D-skin infection models. We could show a strong suppression of cytokine and chemokine response induced by lipopolysacharide (LPS) and Candida albicans for individual compounds. The development of human-based immune responsive assays provides a more accurate and reliable basis for development of new anti-inflammatory or immune-modulating drugs.