Molecular Docking and NMR Binding Studies to Identify Novel Inhibitors of Human Phosphomevalonate Kinase

Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using autodock. Promising hits were verified and their affinity measured using NMR-based 1H–15N heteronuclear single quantum coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (Kd). Tight binding compounds with Kd’s ranging from 6–60 μM were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC cross peak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development

Solution Structures of \u3cem\u3eMycobacterium tuberculosis\u3c/em\u3e Thioredoxin C and Models of Intact Thioredoxin System Suggest New Approaches to Inhibitor and Drug Design

Here, we report the NMR solution structures of Mycobacterium tuberculosis (M. tuberculosis) thioredoxin C in both oxidized and reduced states, with discussion of structural changes that occur in going between redox states. The NMR solution structure of the oxidized TrxC corresponds closely to that of the crystal structure, except in the C-terminal region. It appears that crystal packing effects have caused an artifactual shift in the α4 helix in the previously reported crystal structure, compared with the solution structure. On the basis of these TrxC structures, chemical shift mapping, a previously reported crystal structure of the M. tuberculosis thioredoxin reductase (not bound to a Trx) and structures for intermediates in the E. coli thioredoxin catalytic cycle, we have modeled the complete M. tuberculosis thioredoxin system for the various steps in the catalytic cycle. These structures and models reveal pockets at the TrxR/TrxC interface in various steps in the catalytic cycle, which can be targeted in the design of uncompetitive inhibitors as potential anti-mycobacterial agents, or as chemical genetic probes of function

The CSDDD, Corporate Governance and Jadar Lithium

This paper is about the types of undertakings that will be subject to CSDDD obligations, the substantive and procedural due diligence requirements applicable to these undertakings, and the consequences thereof for the internal governance of groups of companies. The theoretical framework will be tested against the Rio Tinto project to open a lithium mine in the Serbian Jadar valley, which entails substantial risks for people and the environment. CSDDD obligations relating to this project will, inter alia, apply to the top holdings of Rio Tinto and indirect lithium buyers such as Mercedes-Benz and Stellantis, as well as certain operational subsidiaries thereof. It will be laid bare that, in terms of substantive due diligence requirements, the CSDDD and the international treaties it refers to include many open norms. This leaves CSDDD undertakings with some room for judgement and balancing interests. Much of the legal focus will be on the procedural due diligence mandated by the CSDDD. This provides a corporate governance character to the CSDDD. The required 'meaningful engagement' with stakeholders will be important. Also, CSDDD undertakings will be held accountable for both their own activities and the activities of their subsidiaries. They control their subsidiaries and will be expected to impose proper CSDDD policies on them. Thus, the CSDDD will contribute to further developing the doctrine of intragroup governance. Technically, the CSDDD is a fine piece of work. Whether it will actually move the needle for people, the environment and climate will remain to be seen. The Omnibus-proposal presented by the European Commission on 26 February 2025, including some proposed changes to the CSDDD, is not discussed and has no material impact on the findings in this paper.</p

Comparative Legal Analysis of the Corporate Sustainability Due Diligence Directive and Germany´s Supply Chain Due Diligence Act: Implications for National Compliance and Harmonization

This thesis critically examines the Corporate Sustainability Due Diligence Directive (CSDDD) as a transformative legal instrument within the European Union, specifically analyzing its implications for Germany's existing Supply Chain Due Diligence Act (LkSG). The main objective is to analyze and evaluate how the CSDDD reshapes the obligations of companies concerning human rights and environmental impacts, thereby requiring significant changes to the German legal framework. By conducting a thorough comparative analysis, the research identifies key differences in the scope, due diligence requirements, and enforcement mechanisms between the CSDDD and the LkSG. The analysis reveals that while both frameworks share a common goal of preventing human rights violations and environmental harm in global supply chains, the CSDDD extends these obligations, broadening the scope to include indirect suppliers and introducing stricter due diligence obligations. The thesis explores the challenges Germany faces in integrating the CSDDD, particularly in areas where the directive imposes more stringent requirements or introduces new obligations that conflict with the current national legislation. Additionally, a range of concerns surrounding both the CSDDD and the LkSG are addressed, highlighting various challenges and limitations in their design and implementation. Through this analysis, the thesis provides a comprehensive understanding of the necessary legal adaptations required for Germany to fully align the LkSG with the CSDDD. The findings contribute to the broader discourse on corporate sustainability and human rights, offering insights into the evolving landscape of EU regulations and their impact on national legal systems.Esta tese examina criticamente a Diretiva de Dever de Diligência em Sustentabilidade Corporativa (CSDDD) como um instrumento legal transformador dentro da União Europeia, analisando especificamente suas implicações para a Lei Alemã de Dever de Diligência nas Cadeias de Suprimento (LkSG). O principal objetivo é analisar e avaliar como a CSDDD redefine as obrigações das empresas em relação aos direitos humanos e aos impactos ambientais, exigindo, assim, mudanças significativas no quadro jurídico alemão. Através de uma análise comparativa detalhada, a pesquisa identifica diferenças-chave no escopo, nas exigências de diligência devida e nos mecanismos de aplicação entre a CSDDD e a LkSG. A análise revela que, embora ambos os marcos compartilhem o objetivo comum de prevenir violações de direitos humanos e danos ambientais nas cadeias de suprimento globais, a CSDDD amplia essas obrigações, expandindo o escopo para incluir fornecedores indiretos e introduzindo obrigações de diligência devida mais rigorosas. A tese explora os desafios que a Alemanha enfrenta na integração da CSDDD, particularmente em áreas onde a Diretiva impõe requisitos mais estritos ou introduz novas obrigações que entram em conflito com a legislação nacional vigente. Além disso, são abordadas várias preocupações relacionadas tanto à CSDDD quanto à LkSG, destacando os diversos desafios e limitações em seu design e implementação. Por meio dessa análise, a tese proporciona uma compreensão abrangente das adaptações jurídicas necessárias para que a Alemanha alinhe plenamente a LkSG com a CSDDD. As conclusões contribuem para o discurso mais amplo sobre sustentabilidade corporativa e direitos humanos, oferecendo insights sobre o cenário evolutivo das regulamentações da UE e seu impacto nos sistemas jurídicos nacionais

The newly-adopted Corporate Sustainability Due Diligence Directive: an overview of the lawmaking process and analysis of the final text

This article provides an overview of the process leading up to the adoption of the Corporate Sustainability Due Diligence Directive (CSDDD) and delivers a comprehensive analysis of the Directive’s final text. The article contextualises the design process of the CSDDD within the international normative framework on sustainability due diligence and elaborates on key events surrounding the inter-institutional negotiations between the European Commission, the European Parliament and the Council of the European Union on the Directive. The article then delves into the content of the newly adopted text, highlighting key differences between the final version and the Commission’s original proposal

CORPORATE SUSTAINABILITY AND EU LEGISLATION An Analysis of the Influence of the CSRD and the CSDDD on Environmental Collective Action by Companies in the Netherlands

In recent years, the role of companies in climate change mitigation has gained significant attention, yet motivating companies to undertake environmental actions remains challenging. This study examines corporate sustainability from the theoretical perspective of large-scale collective action. Within this theory, stressors counteracting opportunities for collective action and facilitators enhancing such efforts have been identified, and it has been argued that third-party intervention is needed to mitigate stressors and amplify facilitators. In the literature, the influence of EU legislation on environmental collective action by companies has so far been overlooked. This research addresses this gap by analyzing the influence of two recently adopted EU directives, the Corporate Sustainability Reporting Directive (CSRD) and the Corporate Sustainability Due Diligence Directive (CSDDD), on corporate sustainability. The study consists of two separate parts. First, through document analysis, five main ways in which the CSRD and the CSDDD address large-scale collective action are identified: standardization, transparency, communication, power and punishment, and accountability. Second, semi-structured interviews with 13 large Dutch companies explore companies’ perspectives on how these directives influence relevant stressors and facilitators of corporate environmental action. The results show that companies perceive a largely positive influence on the influence of the CSRD and the CSDDD on the themes identified from the document analysis, even though there are important limitations to the directives’ influence that need consideration. In addition, competition, legal uncertainty, resources, and personal and social norms are newly identified themes regarding the influence of the CSRD and the CSDDD on corporate sustainability

Practical Implications of the CSDDD: A Threat to its Effectiveness

• Amending the concept of "value chain" to "chain of activities" (see section 3.1);• Amending the concept of "established business relationship" to "business partner" (see sections 2 and 3.1); and• Amendments to the civil liability regime (see sections 2.4 and 4.2).The CSDDD is expected to have significant practical implications for many companies and their value chains. From field research (questionnaires and follow-up discussions held with large companies in the scope of the proposed CSDDD, both listed and non-listed and including financial institutions) we have distilled the most pertinent practical implications that companies expect. This contribution discusses these expected practical implications. Although the relevant companies applaud the general aim and purpose of what the CSDDD seeks to accomplish, they also point to a number of significant shortcomings that will hamper its application in practice. These include the uncertainty of many of the expected effects and the ambiguity of many key terms and provisions of both the Commission Proposal and the Political Compromise. This may undermine the CSDDD's goal and effectiveness and already currently causes companies to incur difficulties in achieving operational and contractual readiness

Corporate Sustainability Reporting : Shifting From Optional Due Diligence to Mandatory Duty

This paper offers a critical overview of the newly proposed Corporate Sustainability Due Diligence Directive by the European Commission. The aim is to uncover potential opportunities, challenges, gaps, and contradictions, within the directive. We provide insights on how companies can effectively navigate through these issues and leverage upon the directive for more environmentally friendly and ethically sound operations within the global value chain. Ultimately, our aim is to offer researchers, managers, and policymakers a viewpoint on the potential impacts of the new directive on organizations and provide future research directions around responsible corporate conduct across global value chains.© 2024 The Author(s). Business Ethics, the Environment & Responsibility published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.fi=vertaisarvioitu|en=peerReviewed

The Draft Directive on Corporate Sustainability Due Diligence

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