The selective targeting of lung, liver, and kidney tissues presents both a significant challenge and a promising opportunity in medicinal chemistry. This review explores drug design strategies aimed at achieving tissue specificity, using detailed case studies to highlight the practical applications and successes of these approaches in both clinical and preclinical settings. In this chapter we provide a comprehensive overview of current advancements and outline future directions in the field.
The arrival of AlphaFold marked a new era in structural biology, with this transformative AI technology now reshaping the landscape of drug design. In this chapter we discuss advances across the drug design process, including target identification and validation, the acceleration of hit-finding campaigns through virtual screening, and the enablement of structure-based drug design. We explore the exciting frontiers of modulating protein-protein interactions, the rational discovery of molecular glues, and antibody drug design. While celebrating remarkable progress, we also acknowledge the current limitations of these models. This chapter offers a narrative of a rapidly evolving field, showing how AI-driven structural insights are deepening our understanding of biology and will enable the design of novel therapeutics with unprecedented precision and speed.
This review article explores the pivotal role of conformational drivers in the discovery of drug-like molecules and illustrates their significance through real-life examples. Understanding molecular conformation is paramount to drug hunting as it can impact on- and off-target potency, metabolism, permeability, and solubility. Each conformational driver or effector is described and exemplified in a separate section. The final section is dedicated to NMR spectroscopy and illustrates its utility as an essential tool for conformational design.
Malaria remains a devastating but preventable infectious disease that disproportionately affects the African continent. Emerging resistance to current frontline therapies means that not only are new treatments urgently required, but also novel validated antimalarial targets to circumvent cross-resistance. Fortunately, tremendous efforts have been made by the global drug discovery community over the past decade. In this chapter, we will highlight some of the antimalarial drug discovery and development programmes currently underway across the globe, charting progress in the identification of new targets and the development of new classes of drugs to prosecute them. These efforts have been complemented by the development of valuable tools to accelerate target validation such as the NOD scid gamma (NSG) humanized mouse efficacy model and progress in predictive modelling and open-source software. Among the medicinal chemistry programmes that have been conducted over the past decade are those targeting Plasmodium falciparum ATPase4 (ATP4) and acetyl-CoA synthetase (AcAS) as well as proteins disrupting parasite protein translation such as the aminoacyl-tRNA synthetases (aaRSs) and eukaryotic elongation factor 2 (eEF2). The benefits and challenges of targeting Plasmodium kinases will be examined, with a focus on Plasmodium cyclic GMP-dependent protein kinase (PKG), cyclin-dependent-like protein kinase 3 (CLK3) and phosphatidylinositol 4-kinase (PI4K). The chapter concludes with a survey of incipient drug discovery centres in Africa and acknowledges the value of recent international meetings in galvanizing and uniting the antimalarial drug discovery community.
The field of induced proximity therapeutics has expanded dramatically over the past 3 years, and heterobifunctional derivatives continue to form a significant component of the activities in this field. Here, we review recent advances in the field from the perspective of the medicinal chemist, with a particular focus upon informative case studies, alongside a review of emerging topics such as Direct-To-Biology (D2B) methodology and utilities for heterobifunctional compounds beyond E3 ligase mediated degradation. We also include a critical evaluation of the latest thinking around the optimisation of physicochemical and pharmacokinetic attributes of these beyond Role of Five molecules, to deliver appropriate therapeutic exposure in vivo.
