Computational methodologies applied to Protein-Protein Interactions for molecular insights in Medicinal Chemistry

In living systems, proteins usually team up into \u201cmolecular machinery\u201d implementing several protein-to-protein physical contacts \u2013 or protein-protein interactions (PPIs) \u2013 to exert biological effects at both cellular and systems levels. Deregulations of protein-protein contacts have been associated with a huge number of diseases in a wide range of medical areas, such as oncology, cancer immunotherapy, infectious diseases, neurological disorders, heart failure, inflammation and oxidative stress. PPIs are very complex and usually characterised by specific shape, size and complementarity. The protein interfaces are generally large, broad and shallow, and frequently protein-protein contacts are established between non-continuous epitopes, that conversely are dislocated across the protein interfaces. For this reason, in the past two decades, PPIs were thought to be \u201cundruggable\u201d targets by the scientific research community with scarce or no chance of success. However, in recent years the Medicinal Chemistry frontiers have been changing and PPIs have gained popularity amongst the research groups due to their key roles in such a huge number of diseases. Until recently, PPIs were determined by experimental evidence through techniques specifically developed to target a small group of interactions. However, these methods present several limitations in terms of high costs and labour- and time-wasting. Nowadays, a large number of computational methods have been successfully applied to evaluate, validate, and deeply analyse the experimentally determined protein interactomes. In this context, a high number of computational tools and techniques have been developed, such as methods designed to construct interaction databases, quantum mechanics and molecular mechanics (QM/MM) to study the electronic properties, simulate chemical reactions, and calculate spectra, and all-atom molecular dynamics simulations to simulate temporal and spatial scales of inter- and intramolecular interactions. These techniques have allowed to explore PPI networks and predict the related functional features. In this PhD work, an extensive use of computational techniques has been reported as valuable tool to explore protein-protein interfaces, identify their hot spot residues, select small molecules and design peptides with the aim of inhibiting six different studied PPIs. Indeed, in this thesis, a success story of in silico approaches to PPI study has been described, where MD simulations, docking and pharmacophore screenings led to the identification of a set of PPI modulators. Among these, two molecules, RIM430 and RIM442, registered good inhibitory activity with IC50 values even within the nanomolar range against the interaction between MUC1 and CIN85 proteins in cancer disease. Furthermore, computational alanine scanning, all-atom molecular dynamics simulations, docking and pharmacophore screening were exploited to (1) rationally predict three potential interaction models of NLRP3PYD-ASCPYD complex involved in inflammatory and autoimmune diseases; (2) identify a potentially druggable region on the surface of SARS-CoV-2 Spike protein interface and select putative inhibitors of the interaction between Spike protein and the host ACE2 receptor against COVID-19 (CoronaVIrus Disease 2019); (3) investigate intramolecular modifications as a consequence of a point mutation on C3b protein (R102G) associated with the age-related macular degeneration (AMD) disease; (4) design non-standard peptides to inhibit transcriptional events associated with HOX-PBX complex involved in cancer diseases; and (5) to optimise a patented peptide sequence by designing helix-shaped peptides embedded with the hydrogen bond surrogate approach to tackle cocaine abuse relapses associated with Ras-RasGRF1 interaction. Although all the herein exploited techniques are based on predictive calculations and need experimental evidence to confirm the findings, the results and molecular insights retrieved and collected show the potential of the computer-aided drug design applied to the Medicinal Chemistry, guaranteeing labour- and time-saving to the research groups. On the other hand, computing ability, improved algorithms and fast-growing data sets are rapidly fostering advances in multiscale molecular modelling, providing a powerful emerging paradigm for drug discovery. It means that more and more research efforts will be done to invest in novel and more precise computational techniques and fine-tune the currently employed methodologies

Proceedings of the Second International Mobile Satellite Conference (IMSC 1990)

Presented here are the proceedings of the Second International Mobile Satellite Conference (IMSC), held June 17-20, 1990 in Ottawa, Canada. Topics covered include future mobile satellite communications concepts, aeronautical applications, modulation and coding, propagation and experimental systems, mobile terminal equipment, network architecture and control, regulatory and policy considerations, vehicle antennas, and speech compression

Princeton Plasma Physics Laboratory annual report, October 1, 1993-- September 30, 1994

The Tokamak Fusion Test Reactor (TFTR) project is well into the experimental phase of its deuterium-tritium (D-T) program, with the objective to derive the maximum amount of experimental data on the behavior of tokamak plasmas containing a significant population of energetic alpha particles. Since the initial D-T experiments in December 1993, the operational performance of the TFTR, as well as the required tritium-handling and machine maintenance procedures in an activated environment, have improved markedly, so that D-T operation has now become essentially routine, while fully conforming with all of the safety and environmental requirements. During the D-T phase, the machine and auxiliary-systems parameters have also been increased, most notably the toroidal field (to 5.6 T) and the neutral-beam power (to 40 MW). The radio-frequency power in the ion-cyclotron-range of frequencies (ICRF) has been increased to 11 MW

Proceedings of the Fifth International Mobile Satellite Conference 1997

Satellite-based mobile communications systems provide voice and data communications to users over a vast geographic area. The users may communicate via mobile or hand-held terminals, which may also provide access to terrestrial communications services. While previous International Mobile Satellite Conferences have concentrated on technical advances and the increasing worldwide commercial activities, this conference focuses on the next generation of mobile satellite services. The approximately 80 papers included here cover sessions in the following areas: networking and protocols; code division multiple access technologies; demand, economics and technology issues; current and planned systems; propagation; terminal technology; modulation and coding advances; spacecraft technology; advanced systems; and applications and experiments

Nuclear Power - Control, Reliability and Human Factors

Advances in reactor designs, materials and human-machine interfaces guarantee safety and reliability of emerging reactor technologies, eliminating possibilities for high-consequence human errors as those which have occurred in the past. New instrumentation and control technologies based in digital systems, novel sensors and measurement approaches facilitate safety, reliability and economic competitiveness of nuclear power options. Autonomous operation scenarios are becoming increasingly popular to consider for small modular systems. This book belongs to a series of books on nuclear power published by InTech. It consists of four major sections and contains twenty-one chapters on topics from key subject areas pertinent to instrumentation and control, operation reliability, system aging and human-machine interfaces. The book targets a broad potential readership group - students, researchers and specialists in the field - who are interested in learning about nuclear power

Proceedings of the Third International Mobile Satellite Conference (IMSC 1993)

Satellite-based mobile communications systems provide voice and data communications to users over a vast geographic area. The users may communicate via mobile or hand-held terminals, which may also provide access to terrestrial cellular communications services. While the first and second International Mobile Satellite Conferences (IMSC) mostly concentrated on technical advances, this Third IMSC also focuses on the increasing worldwide commercial activities in Mobile Satellite Services. Because of the large service areas provided by such systems, it is important to consider political and regulatory issues in addition to technical and user requirements issues. Topics covered include: the direct broadcast of audio programming from satellites; spacecraft technology; regulatory and policy considerations; advanced system concepts and analysis; propagation; and user requirements and applications