Integration of advanced methods and models to study drug absorption and related processes : An UNGAP perspective

Funding Information: AI acknowledges the support of projects icp009 (ALKOOL) of PRACE-ICEI (grant agreement 800858) for awarding access to Piz Daint, at the Swiss National Supercomputing Centre (CSCS), Switzerland and BG05M2OP001–1.001–0004 (UNITe) of the Bulgarian Ministry of Education and Science. For further details on points raised in this article, please contact [email protected]. Funding Information: Acknowledgements. JAGH is supported by the Biocenter Finland, the Helsinki Institute of Life Sciences, and the Faculty of Pharmacy, University of Helsinki. Publisher Copyright: © 2021 The AuthorsThis collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.Peer reviewe

Molecular dynamics, crystallography and mutagenesis studies on the substrate gating mechanism of prolyl oligopeptidase

Altered prolyl oligopeptidase (PREP) activity is found in many common neurological and other genetic disorders, and in some cases PREP inhibition may be a promising treatment. The active site of PREP resides in an internal cavity; in addition to the direct interaction between active site and substrate or inhibitor, the pathway to reach the active site (the gating mechanism) must be understood for more rational inhibitor design and understanding PREP function. The gating mechanism of PREP has been investigated through molecular dynamics (MD) simulation combined with crystallographic and mutagenesis studies. The MD results indicate the inter-domain loop structure, comprised of 3 loops at residues, 189–209 (loop A), 577–608 (loop B), and 636–646 (loop C) (porcine PREP numbering), are important components of the gating mechanism. The results from enzyme kinetics of PREP variants also support this hypothesis: When loop A is (1) locked to loop B through a disulphide bridge, all enzyme activity is halted, (2) nicked, enzyme activity is increased, and (3) removed, enzyme activity is only reduced. Limited proteolysis study also supports the hypothesis of a loop A driven gating mechanism. The MD results show a stable network of H-bonds that hold the two protein domains together. Crystallographic study indicates that a set of known PREP inhibitors inhabit a common binding conformation, and this H-bond network is not significantly altered. Thus the domain separation, seen to occur in lower taxa, is not involved in the gating mechanism for mammalian PREP. In two of the MD simulations we observed a conformational change that involved the breaking of the H-bond network holding loops A and B together. We also found that this network was more stable when the active site was occupied, thus decreasing the likelihood of this transition

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.QC 20220222</p

Issues About the Physiological Functions of Prolyl Oligopeptidase Based on Its Discordant Spatial Association With Substrates and Inconsistencies Among mRNA, Protein Levels, and Enzymatic Activity

Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyses proline-containing peptides shorter than 30 amino acids. POP may be associated with cognitive functions, possibly via the cleavage of neuropeptides. Recent studies have also suggested novel non-hydrolytic and non-catalytic functions for POP. Moreover, POP has also been proposed as a regulator of inositol 1,4,5-triphosphate signaling and several other functions such as cell proliferation and differentiation, as well as signal transduction in the central nervous system, and it is suspected to be involved in pathological conditions such as Parkinson's and Alzheimer's diseases and cancer. POP inhibitors have been developed to restore the depleted neuropeptide levels encountered in aging or in neurodegenerative disorders. These compounds have shown some antiamnesic effects in animal models. However, the mechanisms of these hypothesized actions are still far from clear. Moreover, the physiological role of POP has remained unknown, and a lack of basic studies, including its distribution, is obvious. The aim of this review is to gather information about POP and to propose some novel roles for this enzyme based on its distribution and its discordant spatial association with its best known substrates. (J Histochem Cytochem 57:831–848, 2009

International Ignatian Reconciliation Conference: From crisis and confrontation to healing and forgiveness, how is reconciliation possible?

El compromiso de la Compañía de Jesús en el quehacer universitario se expresa en el deseo de contribuir efectivamente a hacer posible una vida digna, plena, para todos y cada uno de los seres humanos, en el presente y en el futuro. Para lograr una vida digna, una vida plena, se requiere la reconciliación. Por ello, la Universidad jesuita debe ser una fuente de vida, comprometida a fondo en los procesos de reconciliación. La Universidad Pontificia Comillas y la Pontificia Universidad Javeriana trabajaron bajo la orientación y el estímulo del padre Michael J. Garanzini, S. J. en la organización de la Conferencia Internacional de Reconciliación Ignaciana de la Crisis y el Enfrentamiento a la Sanación y el Perdón: ¿Cómo es Posible la Reconciliación?, que se realizó del 10 al 12 de mayo de 2021, en modalidad combinada (presencial y remota), desde Madrid. En esta, además de abordajes conceptuales sobre la reconciliación, se presentaron experiencias consolidadas en territorios o con comunidades específicas de construcción de paz y reconciliación de instituciones vinculadas a la Compañía de Jesús. Las memorias de la Conferencia que aquí presentamos tienen el fin de contribuir a que las conversaciones de perdón se den y se multipliquen, de modo que la reconstrucción del tejido social deje de ser una utopía para convertirse en una posibilidad palpable. Sin más, esta Conferencia fue el resultado de esa unión por la que tanto propende la reconciliación, pues no debemos olvidar que parte del proceso para llegar a ella nace del amor y de una meta por trascender todo aquello que nos divide y que, en este caso, se hace desde unas universidades comprometidas y de la mano del legado espiritual de san Ignacio.The commitment of the Society of Jesus in university work is expressed in the desire to effectively contribute to making possible a dignified, full life for each and every one of the human beings, in the present and in the future. To achieve a dignified life, a full life, reconciliation is required. For this reason, the Jesuit University must be a source of life, fully committed to reconciliation processes. Comillas Pontifical University and Javeriana Pontifical University worked under the guidance and encouragement of Father Michael J. Garanzini, S.J. in organizing the International Conference on Ignatian Reconciliation from Crisis and Confrontation to Healing and Forgiveness: How is Possible Reconciliation?, which took place from May 10 to 12, 2021, in a combined modality (face-to-face and remote), from Madrid. In this, in addition to conceptual approaches on reconciliation, consolidated experiences in territories or with specific communities of peacebuilding and reconciliation of institutions linked to the Society of Jesus were presented. The Conference proceedings that we present here have the purpose of contributing to the conversations of forgiveness occurring and multiplying, so that the reconstruction of the social fabric ceases to be a utopia and becomes a palpable possibility. Without further ado, this Conference was the result of that union for which reconciliation tends so much, because we must not forget that part of the process to reach it is born of love and of a goal to transcend everything that divides us and that, in this case, it is done from committed universities and hand in hand with the spiritual legacy of Saint Ignatius.Madri