Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing.

Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.

Three-dimensional saturated C(sp)-rich bioisosteres for benzene.

Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes.

Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.

The maintenance of cholesterol homeostasis is crucial for normal function at both the cellular and organismal levels. Two integral membrane proteins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and Scap, are key targets of a complex feedback regulatory system that operates to ensure cholesterol homeostasis. HMGCR catalyzes the rate-limiting step in the transformation of the 2-carbon precursor acetate to 27-carbon cholesterol.