Showing papers by "Dimitris Maroulis published in 2020"

Antibody Clustering Using a Machine Learning Pipeline that Fuses Genetic, Structural, and Physicochemical Properties.

Abstract: Antibody V domain clustering is of paramount importance to a repertoire of immunology-related areas. Although several approaches have been proposed for antibody clustering, still no consensus has been reached. Numerous attempts use information from genes, protein sequences, 3D structures, and 3D surfaces in an effort to elucidate unknown action mechanisms directly related to their function and to either link them directly to diseases or drive the discovery of new medicines, such as antibody drug conjugates (ADC). Herein, we describe a new V domain antibody clustering method based on the comparison of the interaction sites between each antibody and its antigen. A more specific clustering analysis of the antibody's V domain was provided using deep learning and data mining techniques. The multidimensional information was extracted from the structural resolved antibodies when they were captured to interact with other proteins. The available 3D structures of protein antigen-antibody (Ag-Ab) interfaces contain information about how antibody V domains recognize antigens as well as about which amino acids are involved in the recognition. As such, the antibody surface holds information about antigens' folding that reside with the Ab-Ag interface residues and how they interact. In order to gain insight into the nature of such interactions, we propose a new simple philosophy to transform the conserved framework (fragment regions, complementarity-determining regions) of antibody V domain in a binary form using structural features of antibody-antigen interactions, toward identifying new antibody signatures in V domain binding activity. Finally, an advanced three-level hybrid classification scheme has been set for clustering antibodies in subgroups, which can combine the information from the protein sequences, the three-dimensional structures, and specific "key patterns" of recognized interactions. The clusters provide multilevel information about antibodies and antibody-antigen complexes.

Drugena: A Fully Automated Immunoinformatics Platform for the Design of Antibody-Drug Conjugates Against Neurodegenerative Diseases.

Abstract: Antibodies are proteins that are the first line of defense in the adaptive immune response of vertebrates. Thereby, they are involved in a multitude of biochemical mechanisms and clinical manifestations with significant medical interest, such as autoimmunity, the regulation of infection, and cancer. An emerging field in antibody science that is of huge medicinal interest is the development of novel antibody-interacting drugs. Such entities are the antibody-drug conjugates (ADCs), which are a new type of targeted therapy, which consist of an antibody linked to a payload drug. Overall, the underlying principle of ADCs is the discerning delivery of a drug to a target, hoping to increase the potency of the original drug. Drugena suite is a pioneering platform that employs state-of-the-art computational biology methods in the fight against neurodegenerative diseases using ADCs. Drugena encompasses an up-to-date structural database of specialized antibodies for neurological disorders and the NCI database with over 96 million entities for the in silico development of ADCs. The pipeline of the Drugena suite has been divided into several steps and modules that are closely related with a synergistic fashion under a user-friendly graphical user interface.