96 research outputs found
Artificial Intelligence for Science in Quantum, Atomistic, and Continuum Systems
Advances in artificial intelligence (AI) are fueling a new paradigm of
discoveries in natural sciences. Today, AI has started to advance natural
sciences by improving, accelerating, and enabling our understanding of natural
phenomena at a wide range of spatial and temporal scales, giving rise to a new
area of research known as AI for science (AI4Science). Being an emerging
research paradigm, AI4Science is unique in that it is an enormous and highly
interdisciplinary area. Thus, a unified and technical treatment of this field
is needed yet challenging. This work aims to provide a technically thorough
account of a subarea of AI4Science; namely, AI for quantum, atomistic, and
continuum systems. These areas aim at understanding the physical world from the
subatomic (wavefunctions and electron density), atomic (molecules, proteins,
materials, and interactions), to macro (fluids, climate, and subsurface) scales
and form an important subarea of AI4Science. A unique advantage of focusing on
these areas is that they largely share a common set of challenges, thereby
allowing a unified and foundational treatment. A key common challenge is how to
capture physics first principles, especially symmetries, in natural systems by
deep learning methods. We provide an in-depth yet intuitive account of
techniques to achieve equivariance to symmetry transformations. We also discuss
other common technical challenges, including explainability,
out-of-distribution generalization, knowledge transfer with foundation and
large language models, and uncertainty quantification. To facilitate learning
and education, we provide categorized lists of resources that we found to be
useful. We strive to be thorough and unified and hope this initial effort may
trigger more community interests and efforts to further advance AI4Science
XVI Agricultural Science Congress 2023: Transformation of Agri-Food Systems for Achieving Sustainable Development Goals
The XVI Agricultural Science Congress being jointly organized by the National Academy of Agricultural Sciences
(NAAS) and the Indian Council of Agricultural Research (ICAR) during 10-13 October 2023, at hotel Le Meridien,
Kochi, is a mega event echoing the theme “Transformation of Agri-Food Systems for achieving Sustainable
Development Goals”. ICAR-Central Marine Fisheries Research Institute takes great pride in hosting the XVI ASC,
which will be the perfect point of convergence of academicians, researchers, students, farmers, fishers, traders,
entrepreneurs, and other stakeholders involved in agri-production systems that ensure food and nutritional security
for a burgeoning population.
With impeding challenges like growing urbanization, increasing unemployment, growing population, increasing
food demands, degradation of natural resources through human interference, climate change impacts and natural
calamities, the challenges ahead for India to achieve the Sustainable Development Goals (SDGs) set out by the
United Nations are many. The XVI ASC will provide an interface for dissemination of useful information across all
sectors of stakeholders invested in developing India’s agri-food systems, not only to meet the SDGs, but also to
ensure a stable structure on par with agri-food systems around the world.
It is an honour to present this Book of Abstracts which is a compilation of a total of 668 abstracts that convey the
results of R&D programs being done in India. The abstracts have been categorized under 10 major Themes – 1.
Ensuring Food & Nutritional Security: Production, Consumption and Value addition; 2. Climate Action for Sustainable
Agri-Food Systems; 3. Frontier Science and emerging Genetic Technologies: Genome, Breeding, Gene Editing;
4. Livestock-based Transformation of Food Systems; 5. Horticulture-based Transformation of Food Systems; 6.
Aquaculture & Fisheries-based Transformation of Food Systems; 7. Nature-based Solutions for Sustainable AgriFood Systems; 8. Next Generation Technologies: Digital Agriculture, Precision Farming and AI-based Systems; 9.
Policies and Institutions for Transforming Agri-Food Systems; 10. International Partnership for Research, Education
and Development.
This Book of Abstracts sets the stage for the mega event itself, which will see a flow of knowledge emanating
from a zeal to transform and push India’s Agri-Food Systems to perform par excellence and achieve not only the
SDGs of the UN but also to rise as a world leader in the sector. I thank and congratulate all the participants who
have submitted abstracts for this mega event, and I also applaud the team that has strived hard to publish this
Book of Abstracts ahead of the event. I wish all the delegates and participants a very vibrant and memorable
time at the XVI ASC
Opioids and Their Receptors
Few neurotransmitter systems have fascinated as much as the opioid system (i.e., opioid ligands and their receptors). Over the years, scientific studies of the endogenous opioid system have uncovered a complex and subtle system that exhibits impressive diversity, based on its critical role in modulating a large number of sensory, motivational, emotional and cognitive functions. Additionally, its important therapeutic value for the treatment of many human disorders, including pain, affective and addictive disorders, and gastrointestinal motility disorders, has been of persistent interest. This book specifically covers a broad area of the opioid research, offering up-to-date and new perspectives about opioid drug discovery. The diversity among the discussed topics ranging from medicinal chemistry to opioid pharmacology, from basic science to translational research, is a testimony to the complexity of the opioid system that results from the expression, regulation and functional role of opioid ligands and their receptors. This book will serve as a useful reference to scientists while also stimulating continuous research in the chemistry and pharmacology of the opioid system, with the prospective for finding improved therapies of human diseases where the opioid system plays a central role
Deorphanizing Human Cytochrome P450 Enzymes CYP4A22 and CYP4Z1 through Mechanistic in silico Modeling
Cytochrome P450 (CYP) enzymes are monooxygenases that catalyze the oxidation of structurally diverse substrates and are present in various lifeforms, including humans. Human CYPs catalyze the metabolism of xenobiotics including drugs and are involved in the essential biosynthesis of steroids, vitamins, and lipids. CYP-catalyzed metabolism and biosynthesis has been extensively studied recently, but several CYPs remain understudied despite their potential role in key biotransformation pathways. For these so-called ‘orphaned CYPs’, physiological function and structure are yet unknown, such as for CYP4A22 and 4Z1. CYP4A22 catalyzes the ω-hydroxylation of arachidonic acid to the angiogenic 20-hydroxyeicosatetraenoic acid. CYP4Z1 is overexpressed in breast cancer and other malignancies, which is correlated with tumor progression. Hence, CYP4Z1 is considered a promising breast cancer target that was not previously addressed by small molecule inhibitors. Here, we report our efforts to deorphanize CYP4A22 and 4Z1 together with our experimental partner Prof. Bureik. We were the first to predict the structure of CYP4A22 and 4Z1 by homology modeling and overcame the challenge of low-sequence similarity templates by incorporating substrate activities. We applied substrate docking and 3D pharmacophore modeling to rationalize how the binding site structure determines structure-activity relationships (SAR) trends. The well-known structural flexibility of CYPs was partially accounted for by molecular dynamics simulations. For the first time, enzyme-substrate interactions dynamics were analyzed with our novel dynamic pharmacophore approach, which led to the prediction of key residues. For CYP4A22, a residue influencing ω-hydroxylation (Phe320) and two binding residues (Arg96 and Arg233) were predicted. For CYP4Z1, the key role of Arg487 and assisting role of Asn381 for substrate binding were predicted, which was validated by in vitro mutational studies. The thereby validated CYP4Z1 model and substrate SAR were used in a virtual screening campaign resulting in a new potent and selective CYP4Z1 inhibitor (IC50: 63 ± 19 nM). Taken together, we established an in vitro/in silico deorphanization protocol that shed light on the structure-function relationships of CYP4A22 and 4Z1. This enabled us to discover a potent inhibitor of CYP4Z1 that will allow further studies on the physiological and pathophysiological role of the enzyme and might be further improved to target CYP4Z1 in a new therapeutical approach. Similar workflows could easily be applied to study other neglected enzymes in metabolism and other biotransformation pathways.Cytochrom P450 (CYP)-Enzyme sind Monooxygenasen, die die Oxidation strukturell diverser Substrate katalysieren und in verschiedenen Lebensformen, einschließlich des Menschen, vorkommen. Menschliche CYPs katalysieren den Metabolismus von Xenobiotika einschließlich Arzneistoffen und sind an der essenziellen Biosynthese von Steroiden, Vitaminen und Lipiden beteiligt. CYP-katalysierter Metabolismus und Biosynthese wurden in der Vergangenheit intensiv untersucht, aber einige CYPs sind trotz ihrer potenziellen Rolle in wichtigen Biotransformationswegen noch wenig erforscht. Für diese so genannten „orphaned“ oder „verwaisten“ CYPs, sind physiologische Funktion und Struktur noch unbekannt, wie z.B. CYP4A22 und 4Z1. CYP4A22 katalysiert die ω-Hydroxylierung von Arachidonsäure zu der angiogenen 20-Hydroxyeicosatetraensäure. CYP4Z1 wird bei Brustkrebs und anderen malignen Erkrankungen überexprimiert, was mit der Tumorprogression korreliert ist. Daher wird CYP4Z1 als ein vielversprechendes Brustkrebs-Target angesehen, das bisher nicht durch niedermolekulare Inhibitoren adressiert wurde. Hier berichten wir über unsere Bemühungen, CYP4A22 und 4Z1 zusammen mit unserem experimentellen Partner Prof. Bureik zu deorphanisieren. Wir waren die Ersten, die die Struktur von CYP4A22 und 4Z1 durch Homologiemodellierung vorhersagten und überwanden die Herausforderung der Templates mit geringer Sequenzähnlichkeit, indem wir Substrataktivitäten mit einbezogen. Wir wendeten Substrat-Docking und 3D-Pharmakophor-Modellierung an, um zu rationalisieren, wie die Struktur der Bindungstasche die Trends der Struktur-Aktivitäts-Beziehungen (SAR) bestimmt. Die bekannte strukturelle Flexibilität von CYPs wurde partiell durch Molekulardynamik-Simulationen berücksichtigt. Zum ersten Mal wurde die Dynamik der Enzym-Substrat-Interaktionen mit unserem neuartigen dynamischen Pharmakophor-Ansatz analysiert, was zur Vorhersage von wichtigen Aminosäuren führte. Für CYP4A22 wurde eine Aminosäure, die die ω-Hydroxylierung beeinflusst (Phe320) und zwei Bindungsaminosäuren (Arg96 und Arg233) vorhergesagt. Für CYP4Z1 wurde die Schlüsselrolle von Arg487 und die unterstützende Rolle von Asn381 für die Substratbindung vorhergesagt, welche durch in vitro Mutationsstudien validiert wurde. Das dadurch validierte CYP4Z1-Modell und die Substrat-SAR wurden in einer virtuellen Screening-Kampagne verwendet, die zu einen neuen potenten und selektiven CYP4Z1-Inhibitor führte (IC50: 63 ± 19 nM). Zusammengenommen haben wir ein in vitro/in silico Deorphanisierungsprotokoll etabliert, welches die Struktur-Funktionsbeziehungen von CYP4A22 und 4Z1 beleuchtet. Dies versetzte uns in die Lage einen potenten Inhibitor von CYP4Z1 zu entdecken, der weitere Studien über die physiologische und pathophysiologische Rolle des Enzyms ermöglichen wird und möglicherweise weiter verbessert werden kann, um CYP4Z1 in einem neuen therapeutischen Ansatz zu adressieren. Ähnliche Arbeitsabläufe könnte leicht angewendet werden, um andere vernachlässigte Enzyme im Metabolismus und anderen Biotransformationswegen zu untersuchen
The 2nd International Electronic Conference on Applied Sciences
This book is focused on the works presented at the 2nd International Electronic Conference on Applied Sciences, organized by Applied Sciences from 15 to 31 October 2021 on the MDPI Sciforum platform. Two decades have passed since the start of the 21st century. The development of sciences and technologies is growing ever faster today than in the previous century. The field of science is expanding, and the structure of science is becoming ever richer. Because of this expansion and fine structure growth, researchers may lose themselves in the deep forest of the ever-increasing frontiers and sub-fields being created. This international conference on the Applied Sciences was started to help scientists conduct their own research into the growth of these frontiers by breaking down barriers and connecting the many sub-fields to cut through this vast forest. These functions will allow researchers to see these frontiers and their surrounding (or quite distant) fields and sub-fields, and give them the opportunity to incubate and develop their knowledge even further with the aid of this multi-dimensional network
Tailoring Toll-like Receptor 8 Ligands for Balancing Immune Response and Inflammation
Toll-like receptors (TLRs) play a central role in innate immunity by recognising
invading pathogens and host-derived danger signals and initiating the inflammatory response. Aberrant TLR response is involved in the pathogenesis of cancers, infections, autoimmune disorders and allergic diseases. Therefore, TLRs represent attractive targets for novel therapeutic agents.
The PhD project's main research aim is to discover novel small molecule modulators of Toll-like receptor 8 (TLR8) and understand their mechanisms of action using computational approaches. TLR8 crystal structure is solved, and several modulators are known from previous drug screens. Therefore, TLR8 is a promising target for rational computer-aided development of novel drug candidates. In the initial phase of the project, the main goal was to study relevant structural features in available crystal structures of TLR8. The focus was on the dimerisation interface because of its role in the binding of ligands and subsequent activation of the receptor. Additionally, we studied the conservation of the relevant structural features across the closely related TLRs. The second part shifts the focus to the binding of the small molecules to TLR8.
We investigated interactions between the known ligands and TLR8 and used it to develop the most plausible 3D pharmacophore model. Subsequently, we employed the developed 3D pharmacophore model in virtual screening to identify novel modulators of TLR8. We identified a pyrimidine-based compound that inhibits TLR8-mediated signalling in the micromolar concentration range. The potent anti-inflammatory and dose-dependent response has been confirmed in a series of derivatives of this initial virtual hit, which allowed for a detailed elucidation of structure-activity relationships (SAR) and more precise description of
the binding mode.
Conclusively, we have developed a novel and promising pyrimidine-based TLR8
inhibitors in silico and confirmed their biological activity, selectivity and low cytotoxicity in vitro. Results from the study on TLR8 represent a solid basis for the future design of small molecule TLR modulators as novel therapeutic agents for modulating immune response and inflammation.Toll-like Rezeptoren (TLRs) spielen eine zentrale Rolle in angeborenen
Immunsystem, indem sie eindringende Pathogene sowie endogene Gefahrensignale erkennen und Entzündungsreaktionen einleiten. TLRs sind an der Pathogenese von Krebserkrankungen, Infektionen, Autoimmunerkrankungen und allergischen Erkrankungen beteiligt. Aus diesem Grund stellen TLRs attraktive Ziele für neue, niedermolekulare Wirkstoffe dar.
Das Hauptziel dieses Promotionsprojekts ist die Entdeckung neuer niedermolekularer Modulatoren des Toll-like-Rezeptors 8 (TLR8) und das Verständnis ihrer Wirkmechanismen mit Hilfe computergestützter Ansätze. Die Kristallstruktur von TLR8 ist verfügbar und mehrere Modulatoren sind aus früheren Wirkstoffscreens bekannt. Daher ist TLR8 ein vielversprechendes Ziel für die rationale computergestützte Entwicklung neuer Wirkstoffkandidaten.
Am Beginn des Projekts bestand das Hauptziel darin, relevante strukturelle Merkmale in den verfügbaren Kristallstrukturen von TLR8 zu untersuchen. Der Fokus lag dabei auf dem Dimerisierungsbereich, da dieser eine wichtige Rolle bei der Bindung von Liganden und der anschließenden Aktivierung des Rezeptors spielt. Zusätzlich untersuchten wir die Konservierung der relevanten Strukturmerkmale über die eng verwandten TLRs hinweg. Der zweite Teil verlagert den Fokus auf die Bindung kleiner Moleküle an TLR8. Wir
untersuchten die Interaktionen zwischen den bekannten Liganden und TLR8 und
entwickelten daraus systemtisch ein 3D-Pharmakophormodell. Anschließend setzten wir das entwickelte 3D-Pharmakophormodell im virtuellen Screening ein, um neuartige Modulatoren des TLR8 zu identifizieren. Wir identifizierten ein Pyrimidin-Analogon, das die TLR8- vermittelte Signalweiterleitung im mikromolaren Konzentrationsbereich hemmt. Die potente entzündungshemmende und dosisabhängige Wirkung wurde in einer kleinen Serie von Analoga bestätigt. Schließlich optimierten wir die identifizierten Pyrimidinverbindungen
weiter, was eine detailliertere Struktur-Aktivitäts-Analyse und eine genauere Aufklärung des Bindungsmodus ermöglichte.
Zusammenfassend haben wir neuartige und vielversprechende TLR8-Inhibitoren auf Pyrimidinbasis in silico entwickelt und ihre in vitro biologische Aktivität, Selektivität und geringe Zytotoxizität bestätigt. Die Ergebnisse der Studie zu TLR8 helfen uns, die Prozesse zu verstehen, die für ein erfolgreiches Wirkstoffdesign auch bei anderen TLR notwendig sind und stellen eine gute Ausgangsbasis dar, um in Zukunft optimierte, niedermolekulare TLR- Modulatoren zu entwickeln und damit Entzündung und die Immunreaktion effizient zu modulieren
Benchmarking and Developing Novel Methods for G Protein-coupled Receptor Ligand Discovery
G protein-coupled receptors (GPCR) are integral membrane proteins mediating responses from extracellular effectors that regulate a diverse set of physiological functions. Consequently, GPCR are the targets of ~34% of current FDA-approved drugs.3 Although it is clear that GPCR are therapeutically significant, discovery of novel drugs for these receptors is often impeded by a lack of known ligands and/or experimentally determined structures for potential drug targets. However, computational techniques have provided paths to overcome these obstacles. As such, this work discusses the development and application of novel computational methods and workflows for GPCR ligand discovery. Chapter 1 provides an overview of current obstacles faced in GPCR ligand discovery and defines ligand- and structure-based computational methods of overcoming these obstacles. Furthermore, chapter 1 outlines methods of hit list generation and refinement and provides a GPCR ligand discovery workflow incorporating computational techniques. In chapter 2, a workflow for modeling GPCR structure incorporating template selection via local sequence similarity and refinement of the structurally variable extracellular loop 2 (ECL2) region is benchmarked. Overall, findings in chapter 2 support the use of local template homology modeling in combination with de novo ECL2 modeling in the presence of a ligand from the template crystal structure to generate GPCR models intended to study ligand binding interactions. Chapter 3 details a method of generating structure-based pharmacophore models via the random selection of functional group fragments placed with Multiple Copy Simultaneous Search (MCSS) that is benchmarked in the context of 8 GPCR targets. When pharmacophore model performance was assessed with enrichment factor (EF) and goodness-of-hit (GH) scoring metrics, pharmacophore models possessing the theoretical maximum EF value were produced in both resolved structures (8 of 8 cases) and homology models (7 of 8 cases). Lastly, chapter 4 details a method of structure-based pharmacophore model generation using MCSS that is applicable to targets with no known ligands. Additionally, a method of pharmacophore model selection via machine learning is discussed. Overall, the work in chapter 4 led to the development of pharmacophore models exhibiting high EF values that were able to be accurately selected with machine learning classifiers
Marine Drug Research in China: Selected Papers from the 15-NASMD Conference
The Book covers this whole field, from the discovery of structurally new and bioactive natural products (including biomacromolecules), from marine macro-/micro-organisms, to the pharmacodynamics, pharmacokinetics, metabolisms, and mechanisms of marine-derived lead compounds, both in vitro and in vivo, along with the synthesis and/or structural optimization of marine-derived lead compounds and their structure–activity relationships. Taken together, this Special Issue reprint not only provides inspiration for the discovery of marine-derived novel bioactive compounds, but also sheds light on the further research and development of marine candidate drugs
HIV-1 integrase inhibitor mutations: analysis of structural and biochemical effects.
Doctoral Degree. University of KwaZulu-Natal, Durban.Introduction.
Combination antiretroviral therapy (cART), composed of drugs from different drug classes, is an effective HIV-1 treatment strategy. As part of cART, integrase strand transfer inhibitors (INSTIs) have become essential drugs and are now recommended for use in first-line, second-line, and subsequent HIV-1 treatment regimens. Though highly potent, the use of first-generation INSTIs Raltegravir and Elvitegravir still resulted in the development of integrase drug resistance mutations. Second-generation INSTIs Dolutegravir, Bictegravir, and Cabotegravir were developed to combat the emerging resistant virus strains to first-generation INSTIs and are considered some of the best antiretroviral drugs in HIV-1 treatment. Despite the fundamental changes and improved performance in second-generation INSTIs, they are not immune to drug resistance. This highlights the need to understand the molecular mechanisms of resistance to INSTIs. This thesis, through a combination of structural and biochemical methods, seeks to understand resistance development in South African HIV-1 subtype C (HIV-1C) viruses and the effect of resistance mutations on enzyme-substrate binding, DNA binding, and 3’ processing.
Methods.
A total of 48 HIV-1C sequences were analyzed in this study, of which 7 had a virologic failure (i.e. plasma viral loads >1000 copies/mL) and 41 were INSTI naïve isolates (32 treatment-naïve South African HIV-1C integrase sequences downloaded from GenBank and 9 INSTI-naïve isolates amplified in our laboratory). Virologic failures were receiving at least 6 months of INSTI-based cART and presented at the King Edward VIII hospital, a 3rd line regimen referral hospital in Durban, South Africa. Viral RNA was extracted, and the integrase region was amplified and sequenced using Sanger sequencing. To investigate the effect of mutations on the integrase structure, wild-type and representative mutant isolates were modeled on the SWISS model online server and visualized in Chimera v1.13.1. Raltegravir, Elvitegravir, and Dolutegravir were docked into each of the structures using the AutoDock-Vina Plugin available on Chimera, and molecular dynamics simulations were conducted using the AMBER 18 package. Integrase biochemical assays were carried out using a wild-type protein and the 3 mutant recombinant proteins that were expressed and purified. Integrase - LTR binding and 3’ processing assays were then performed.
Results.
Only one of the 7 (14,28%) INSTI-treated isolates had major mutations (i.e., G140A and Q148R). In addition, this isolate harboured the E157Q minor mutation and previously identified polymorphisms. Interestingly, S119T & V151I, located near the integrase active site, were only found in INSTI failures. Structural analysis results showed a reduced binding affinity for the mutants, which was supported by their weaker hydrogen-bond interaction compared to the wild-type. Our findings showed that the G140A+Q148R double mutant had the strongest effect on the HIV-1C protein structure and binding of EVG and RAL with binding free energies of -12.49 and -11.45 kcal/mol for EVG and RAL, respectively, which are approximately three times lower than the wild-type binding energy. Biochemical assays performed with purified integrase showed a decrease in integrase-LTR binding for all mutants. The 3’ processing activity was slightly decreased in the mutants compared to the wild-type protein; however, no appreciable differences were observed across the mutant isolates.
Conclusions
Changes near the highly conserved active site residues in HIV-1C integrase core domain and mutations in the 140’s loop have a negative effect on in vitro integrase activity, suggesting that these changes impact viral integration. While they are still few reports of INSTI resistance-associated mutations (RAMs) in South Africa , identification of the G140A+Q148R double mutant for the first time in South African HIV-1 clinical samples, and the identification of S119T and V151I in INSTI-treated patients warrants further investigation. This data broadens the understanding of HIV-1C resistance against INSTIs and adds to the available knowledge of drug resistance mutations that guide therapeutic decisions
Study of the interaction between sialic acid-binding immunoglobulin-type lectins (Siglec) and sialylated glycans for the development of a new generation of immunomodulators.
Glycans and complementary glycan-binding proteins represent essential components in the control of both innate and adaptive immunity. Sialic acids are a family of sugars found on the terminal end of mammalian glycoconjugates; they able to act as marker of self in the immune system, as such residues are absent in most microbes.
Sialic acid-binding immunoglobulin-like lectins, or Siglecs, are cell surface receptors that recognize sialic acids and are known to modulate immune responses, influencing almost every cell in the hematopoietic system. Siglecs are involved in events like cell adhesion and signaling, inhibition or regulation of the immune cell activation, all mediated by the interaction with sialylated ligands. Sialic acid-Siglec interactions have been associated with a broad spectrum of diseases, stretching from autoimmunity to neurodegeneration and cancer. Thus, strategies for a rational modulation of the interactions between Siglecs and sialylated glycans in pathophysiological processes exhibit a great therapeutic potential.
In this context, the present thesis project aimed at the study of the interaction between Siglecs and their cognate sialic acid containing ligands, to disclose the key recognition events underlining host immune suppression or activation. To this end, a multidisciplinary approach combining advanced technologies as ligand-based NMR techniques, including STD-NMR and tr-NOESY, biophysical binding assays and computational methodologies, such as homology modelling docking and MD simulations, was applied to provide an atomistic depiction of the interaction interfaces between various sialoglycans and their receptors.
The described strategy has been employed to characterize the binding features of several receptors of the Siglecs family, namely CD22/Siglec-2, Siglec-10 and Siglec-7. CD22 is a B-cell surface inhibitory protein capable of selectively -(2,6) linked sialylated glycans, thus dampening autoimmune responses against self-antigens. The characterization of complex-type N-glycans by CD22 allowed to describe the conformational behavior of the flexible ligands; the formation of CD22 homo-oligomers on the B-cell surface was also addressed. Furthermore, it was provided a global vision of how the most diffuse neuraminic acid forms of sialylated N-glycans are accomodated in the binding pocket of CD22. Moreover, the elucidation of the binding epitope of a synthetic sialo-mimetic upon CD22 interaction afforded new hints for the design and synthesis of high-affinity ligands of therapeutic relevance against B-cell derived malignancies.
Then, the Siglec-10, an inhibitory receptor that recognize 2,3 and -linked sialoglycans was studied, thus providing the first insights of the molecular mechanisms regulating the interaction between Siglec-10 and naturally occurring sialoglycans.
After that, Siglec-7, a well-established inhibitory receptor that is primarily located on natural killer where it acts as inhibitor of cancer cells cytotoxicity via sialylated ligands binding, has been characterized in the interplay with the oncogenic pathogen F. nucleatum. Indeed, the presence of sialylated lipopolysaccharide (LPS) on certain F. nucleatum strains, hinted that it may have a significant role at the immune interface. The interaction between Siglec-7 and the O-polysaccharide chain from the LPS of F. nucleatum 10953 strain has been depicted, thus delineating a structural binding model that might contribute to explain the etiological role of F. nucleatum in carcinogenesis.
A similar approach was employed to other sialoglycan- related systems, i. e. to dissect the mechanism of sialic acid recognition and hydrolysis by mumps virus hemagglutinin neuraminidase, a viral glycoprotein that plays key roles in virus entry and infection; and to assess the binding of the human macrophage galactose-type lectin (MGL) in the interplay with lipooligosaccharide of E. coli strain R1.
In conclusion, the structural and functional characterization of Siglec- sialylated glycans interaction have allowed the analysis, at a molecular level, of crucial feature of 3D complexes, highlighting the molecular determinants involved in recognition and binding events, that will aid for the development or optimization of molecules for therapeutic targeting of the Siglecs
- …