Tripeptide IRW Upregulates NAMPT Protein Levels in Cells and Obese C57BL/6J Mice.

Nicotinamide adenine dinucleotide (NAD) plays a vital role in cellular processes that govern human health and disease. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in NAD biosynthesis. Thus, boosting NAD level via an increase in NAMPT levels is an attractive approach for countering the effects of aging and metabolic disease.

Discovery of Non-peptide Small Molecule Allosteric Modulators of the Src-family Kinase, Hck.

The eight mammalian Src-family tyrosine kinases are dynamic, multi-domain structures, which adopt distinct "open" and "closed" conformations. In the closed conformation, the regulatory SH3 and SH2 domains pack against the back of the kinase domain, providing allosteric control of kinase activity. Small molecule ligands that engage the regulatory SH3-SH2 region have the potential to modulate Src-family kinase activity for therapeutic advantage.

Electrophilic fatty acids impair RAD51 function and potentiate the effects of DNA-damaging agents on growth of triple-negative breast cells.

Homologous recombination (HR)-directed DNA double-strand break (DSB) repair enables template-directed DNA repair to maintain genomic stability. RAD51 recombinase (RAD51) is a critical component of HR and facilitates DNA strand exchange in DSB repair. We report here that treating triple-negative breast cancer (TNBC) cells with the fatty acid nitroalkene 10-nitro-octadec-9-enoic acid (OA-NO) in combination with the antineoplastic DNA-damaging agents doxorubicin, cisplatin, olaparib, and γ-irradiation (IR) enhances the antiproliferative effects of these agents.

Improving small molecule virtual screening strategies for the next generation of therapeutics.

The new generation of post-genomic targets, such as protein-protein interactions (PPIs), often require new chemotypes not well represented in current compound libraries. This is one reason for why traditional high throughput screening (HTS) approaches are not more successful in delivering medicinal chemistry starting points for PPIs. In silico screening methods of an expanded chemical space are then potential alternatives for developing novel chemical probes to modulate PPIs.

Optimal affinity ranking for automated virtual screening validated in prospective D3R grand challenges.

The goal of virtual screening is to generate a substantially reduced and enriched subset of compounds from a large virtual chemistry space. Critical in these efforts are methods to properly rank the binding affinity of compounds. Prospective evaluations of ranking strategies in the D3R grand challenges show that for targets with deep pockets the best correlations (Spearman ρ ~ 0.

Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge.

Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking ("close"), (b) methods that align or dock to a single receptor ("cross"), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor ("min-cross").

Fidelity, mismatch extension, and proofreading activity of the Plasmodium falciparum apicoplast DNA polymerase.

Plasmodium falciparum, a parasitic organism and one of the causative agents of malaria, contains an unusual organelle called the apicoplast. The apicoplast is a nonphotosynthetic plastid responsible for supplying the parasite with isoprenoid units and is therefore indispensable. Like mitochondria and the chloroplast, the apicoplast contains its own genome and harbors the enzymes responsible for its replication.