Experimental fragment-based drug design

Developers

C. W. Murray, P. J. Hajduk, C. Wang, etc.

Description of the technology

The key step in drug discovery is to discover small molecules that bind to a biological target with high affinity and selectivity. Conventionally, high-throughput screening (HTS) is a routine method to identify initial hit or lead compounds in the pharmaceutical industry. However, HTS has several limitations such as small coverage of drug-like chemical space (106–107 screening compounds versus 1060 drug-like molecules), low hit rates and unfavorable physicochemical properties (e.g., large molecular weight and high hydrophobicity). Thus, the optimization of HTS-derived hits into drug-like candidates could be a difficult task with low efficiency.

As an alternative approach, fragment-based drug design (FBDD) is becoming an efficient method for drug discovery. FBDD constructs novel drug-like lead compounds from small fragments by taking advantages of both random screening and structure-based drug design (SBDD). Compared to HTS, FBDD has several advantages, including sampling a larger chemical space (higher chemical diversity), higher hit rates, and higher ligand efficiency (LE = -log IC50/number of heavy atoms).

The first step of FBDD is to detect weak to moderate binders (5 mM to 1 μM) of the desired target by screening a library containing hundreds to thousands of fragments at a high concentration. The detection methods for fragment screening include nuclear magnetic resonance (NMR), mass spectroscopy (MS) [11, 12], X-ray crystallography [13], and surface plasmon resonance (SPR) spectroscopy [14, 15]. These biophysical techniques are highly sensitive to the relatively weak fragment binders. Then, on the basis of the structural information of the target-fragment complex, various optimization strategies, such as fragment linking, fragment evolution, fragment optimization, and fragment self-assembly, can be used separately or in combination to increase the affinity and drug-likeness of fragment hits [16]. Finally, the lead-to-candidate optimization is technically similar to that of conventional drug design methods [4].

Although FBDD has made a great success in drug discovery [17–19], it still faces some intrinsic limitations and challenges. Firstly, the sampling of a larger region of drug-like space is still required. Despite its better performance than HTS, a FBDD study using a typical library of 103 fragments can only sample approximately the chemical diversity space of 109 molecules. Secondly, current fragment screening methods depend largely on high quality target proteins, expensive equipment, and specific expertise [20], which limits their application to a broader range of targets. For example, the application of FBDD to membrane proteins (e.g., G-protein coupled receptors, GPCRs) remains a significant challenge because of the high demand on the amount, purity and solubility of target proteins for labeling or crystallization [21]. Thirdly, it is difficult for current FBDD methods to treat flexibility and selectivity during fragment detection and optimization [22, 23] because the conformation and key interactions of the original fragment hits may be changed once they are constructed into a new molecule.

Practical application

Although most of the FBDD methods need to be improved, FBDD is a prospective method of drug design.

Laboratories

• Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, (USA).
• Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, (UK)
• College of Chemistry, Fuzhou University, Fuzhou, Fujian, (China)
• Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, (USA)
• Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, (USA)

Links

Publications

• Hajduk, Philip J., and Jonathan Greer. «A decade of fragment-based drug design: strategic advances and lessons learned." Nature reviews Drug discovery 6.3 (2007): 211–219.
• Chessari, Gianni, and Andrew J. Woodhead. «From fragment to clinical candidate-a historical perspective." Drug discovery today 14.13 (2009): 668–675.
• Bembenek, Scott D., Brett A. Tounge, and Charles H. Reynolds. «Ligand efficiency and fragment-based drug discovery." Drug discovery today 14.5 (2009): 278–283.
• Yu, Wenying, et al. «Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design." Journal of medicinal chemistry 56.11 (2013): 4402–4412.
• Chen, Haijun, et al. «Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy." European journal of medicinal chemistry 62 (2013): 498–507.