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The use of methods at molecular scale for the discovery of new potential active ligands, as well as previously unknown binding sites for target proteins, is now an established reality. Literature offers many successful stories of active compounds developed starting from insights obtained in silico and approved by Food and Drug Administration (FDA). One of the most famous examples is raltegravir, a HIV integrase inhibitor, which was developed after the discovery of a previously unknown transient binding area thanks to molecular dynamics simulations. Molecular simulations have the potential to also improve the design and engineering of drug delivery devices, which are still largely based on fundamental conservation equations. Although they can highlight the dominant release mechanism and quantitatively link the release rate to design parameters (size, drug loading, et cetera), their spatial resolution does not allow to fully capture how phenomena at molecular scale influence system behavior. In this scenario, the "computational microscope" offered by simulations at atomic scale can shed light on the impact of molecular interactions on crucial parameters such as release rate and the response of the drug delivery device to external stimuli, providing insights that are difficult or impossible to obtain experimentally. Moreover, the new paradigm brought by nanomedicine further underlined the importance of such computational microscope to study the interactions between nanoparticles and biological components with an unprecedented level of detail. Such knowledge is a fundamental pillar to perform device engineering and to achieve efficient and safe formulations. After a brief theoretical background, this review aims at discussing the potential of molecular simulations for the rational design of drug delivery systems., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The use of molecular markers for inflammation in the gastrointestinal tract could empower optical imaging modalities for early diagnosis and eventually personalized timely treatments. A major hurdle to the widespread use of functional fluorescence imaging is the absence of suitable contrast agents, in particular to be administered via the oral route due to the usual proteolytic susceptibility of the biomarkers. By designing a retro-inverso peptide, starting from a previously described sequence specific for N-cadherin, we achieved resistance to gastrointestinal degradation and even slightly improved specificity towards the target, both in ex vivo and in vivo experimental colitis. Simulations at fundamental molecular level suggested that the introduced retro-inverso modifications did not affect the folding of the peptide, leaving its ability to interact with the binding pocket of the monomeric N-cadherin unaltered, even when fluorescently labeled. Possible further derivatization of this sequence could be envisaged to further extend the potential of the designed retro-inverso peptide as diagnostic or theranostic agent for the oral route., (Copyright © 2017 Elsevier B.V. All rights reserved.)