Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centers in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes. Herein we describe recent fragment-based approaches to a wide range of target types, including Hsp90, β-secretase, and allosteric sites in human immunodeficiency virus protease and fanesyl pyrophosphate synthase. The role of fragment-based approaches in an academic research environment is also examined with an emphasis on neglected diseases such as tuberculosis. The development of a fragment library, the fragment screening process, and the subsequent fragment hit elaboration will be discussed using examples from the literature.

Fragment-based approaches in drug discovery and chemical biology

Bioactive Benzofuran derivatives: A review

Chronic hyperglycemia causes structural alterations of proteins through the Maillard reaction. In diabetes, methylglyoxal (MGO)-induced hydroimidazolones are the predominant modification. In contrast to acute hyperglycemia, mitochondrial respiration is depressed in chronic diabetes. To determine whether MGO-derived protein modifications result in abnormalities in mitochondrial bioenergetics and superoxide formation, proteomics and functional studies were performed in renal cortical mitochondria isolated from rats with 2, 6, and 12 mo of streptozotocin-induced diabetes. MGO-modified proteins belonged to the following two pathways: 1) oxidative phosphorylation and 2) fatty acid beta-oxidation. Two of these proteins were identified as components of respiratory complex III, the major site of superoxide production in health and disease. Mitochondria from rats with diabetes exhibited a diminution of oxidative phosphorylation. A decrease in the respiratory complex III activity was significantly correlated with the quantity of MGO-derived hydroimidazolone present on mitochondrial proteins in both diabetic and control animals. In diabetes, isolated renal mitochondria produced significantly increased quantities of superoxide and showed evidence of oxidative damage. Administration of aminoguanidine improved mitochondrial respiration and complex III activity and decreased oxidative damage to mitochondrial proteins. Therefore, posttranslational modifications of mitochondrial proteins by MGO may represent pathogenic events leading to mitochondria-induced oxidative stress in the kidney in chronic diabetes.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00415.2004

Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(12)00032-6.pdf

Experiences in fragment-based drug discovery.

Privileged structures can bind to a diverse range of targets with high affinities, thus benefiting the discovery of novel bioactive agents. 8-Hydroxyquinoline derivatives represent an important type of “privileged structure”, possessing a rich diversity of biological properties. Numerous encouraging investigations have demonstrated that this privileged structure should be further exploited for therapeutic applications in the future. In view of its predominance, and on the basis of our research interest in this scaffold, an updated and detailed account of the pharmacological properties of 8-hydroxyquinoline derivatives, as well as recent insights from structural biology, are described. Finally, some outlooks on current issues and future directions in this field of research are also provided.

8-Hydroxyquinoline: a privileged structure with a broad-ranging pharmacological potential

The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors.

We have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone.

Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design.

Identification of N2-(1-carboxymethyl)guanine (CMG) as a guanine advanced glycation end product

Sequestrants of AGE precursors comprise amines separated by 2, 3 or 4 carbons. Sequestrants of AGE precursors can be used as pharmaceutical agents and in pharmaceutical compositions. The sequestrants of AGE precursors are particularly useful binding AGE precursors and dietary dicarbonyls in mammals in the gastrointestinal tract for the treatment of ailments such as diabetic nephropathy, chronic renal disease, atherosclerosis, stroke, cataracts, and Alzheimer's disease.

Sequestrants of advanced glycation end product (age) precursors

The invention features compounds of Formula (I), Formula (I)-A and Formula (I)- B as disclosed herein, as well as methods of synthesis, therapy, diagnostics, and assays.

Andrew T Papoulis

Papers

The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors.

Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design.

Identification of N2-(1-carboxymethyl)guanine (CMG) as a guanine advanced glycation end product

Sequestrants of advanced glycation end product (age) precursors

Nampt inhibitors and methods