Toward Rational Fragment-Based Lead Design without 3D Structures

Abstract

Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despite tremendous success rates, FBLD relies on the availability of high-resolution structural information, still a bottleneck in drug discovery programs. To overcome these limitations, we recently demonstrated that the meta-structure approach provides an alternative route to rational lead identification in cases where no 3D structure information about the biological target is available. Combined with information-rich NMR data, this strategy provides valuable information for lead development programs. We demonstrate with several examples the feasibility of the combined NMR and meta-structure approach to devise a rational strategy for fragment evolution without resorting to highly resolved protein complex structures.

Niche Genetic Algorithms are better than traditional Genetic Algorithms for de novo Protein Folding

“…Both can provide high resolution images of the folded-state of a protein but rely on the ability of scientists to purify the protein of interest to concentrations of 1 molar (NMR) to greater than 10 molar (x-ray crystallography), which is not an easy task. The x-ray crystallography method is further complicated by the need to determine the conditions for the growth of crystals of the protein and then waiting for those crystals to grow to a usable size and dimension 10 . The NMR method requires less purified protein, compared to x-ray crystallography; however, it is limited by the size of protein that can be analyzed 10 .…”

Protonation‐dependent conformational variability of intrinsically disordered proteins

“…Compactness is inversely related to local residue solvent‐exposure, whereas local secondary structure values are defined analogously to the NMR secondary Cα chemical shift (α‐helices: positive; β‐sheets: negative). Numerous applications have already demonstrated the applicability of this approach . In this study, we computationally consider the effect of lowering the pH by altering the primary sequence through replacing the negatively charged carboxylate groups of Asp/Glu residues with neutral (hydrogen‐bond donor) amide groups of Asn/Gln residues.…”

“…Numerous applications have already demonstrated the applicability of this approach. [14][15][16][17] In this study, we computationally consider the effect of lowering the pH by altering the primary sequence through replacing the negatively charged carboxylate groups of Asp/ Glu residues with neutral (hydrogen-bond donor) amide groups of Asn/Gln residues. The predictive validity of our meta-structure approach is illustrated by its application to the IDPs BASP1, a tumorsuppressor down regulated by the oncogenic transcription factor Myc, 18 and Tcf4, a transcription factor involved in the Wnt signaling pathway.…”

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

“…For example, Konrat and co-workers described a strategy for using protein meta-analysis and ligand-based nuclear magnetic resonance (NMR) techniques to generate leads against two targets without 3D structures. 11 Similarly, Viola and co-workers reported a systematic chemistry approach to explore fragment-level structure−activity relationships (SAR). 12 The development of other methods to evolve and optimize fragments 13 without structural guidance would certainly expand the generality of the FBDD approach.…”