From Protein Domains to Drug Candidates—Natural Products as Guiding Principles in the Design and Synthesis of Compound Libraries

Abstract

In the continuing effort to find small molecules that alter protein function and ultimately might lead to new drugs, combinatorial chemistry has emerged as a very powerful tool. Contrary to original expectations that large libraries would result in the discovery of many hit and lead structures, it has been recognized that the biological relevance, design, and diversity of the library are more important. As the universe of conceivable compounds is almost infinite, the question arises: where is a biologically validated starting point from which to build a combinatorial library? Nature itself might provide an answer: natural products have been evolved to bind to proteins. Recent results in structural biology and bioinformatics indicate that the number of distinct protein families and folds is fairly limited. Often the same structural domain is used by many proteins in a more or less modified form created by divergent evolution. Recent progress in solid-phase organic synthesis has enabled the synthesis of combinatorial libraries based on the structure of complex natural products. It can be envisioned that natural-product-based combinatorial synthesis may permit hit or lead compounds to be found with enhanced probability and quality.

Pseudolaric Acid B, a Novel Microtubule-Destabilizing Agent That Circumvents Multidrug Resistance Phenotype and Exhibits Antitumor Activity In vivo

“…Within this category, many exhibit adequate efficacy without the need for structural modifications (e.g., paclitaxel), whereas some require synthetic modifications (etoposide) for optimal function. It has been noted that natural products may embody more ''privileged structures'' than purely synthetic chemical libraries (2), and they are a rich resource of new chemical motifs. Therefore, the natural product -based drug discovery program remains an important avenue toward the development of small-molecule therapeutics for cancer as well as other diseases (3).…”

Compound library development guided by protein structure similarity clustering and natural product structure

“…T he most crucial criteria to be met in compound library development for medicinal chemistry and chemical biology research are biological relevance (1,2), drug likeness (3)(4)(5)(6)(7), and diversity (8)(9)(10). To meet these criteria usually potential target proteins are clustered into target families on the basis of functional relatedness and amino acid sequence homology (11).…”

“…Inspired by these observations and the prediction that the number of fold types characteristic for all domains occurring in nature is fairly limited [probably Ϸ1,000 (17)], we recently proposed to employ this conservation in spatial structure as an alternative criterion for clustering in the context of ligand identification and compound library design (1,2). In this approach, the ligand-sensing cores of individual protein domains are grouped on the basis of structural similarity and irrespective of sequence similarity to generate a protein structure similarity cluster (PSSC).…”

Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis

“…The efficient synthesis of the indoloquinolizidine collection furthermore demonstrates that the stereoselective synthesis of NPinspired medium-sized compound collections is within the reach of current synthesis methodology (30). In our experience for such multistep synthesis sequences, solid-phase methodology is advantageous because it allows for efficient removal of the reagents used in the various steps and thereby facilitates purification of the final products.…”