4AHT

Parallel screening of a low molecular weight compound library: do differences in methodology affect hit identification

Summary for 4AHT

• Entry DOI: 10.2210/pdb4aht/pdb
• Related: 4AH9 4AHR 4AHS 4AHU 4AHV
• Descriptor: INTEGRASE, SULFATE ION, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: transferase, fragment screening
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS (HIV)
• Total number of polymer chains: 2
• Total formula weight: 41762.80

Authors

Wielens, J.,Heady, S.J.,Rhodes, D.I.,Mulder, R.J.,Dolezal, O.,Deadman, J.J.,Newman, J.,Chalmers, D.K.,Parker, M.W.,Peat, T.S.,Scanlon, M.J. (deposition date: 2012-02-07, release date: 2012-12-19, Last modification date: 2023-12-20)

Primary citation

Wielens, J.,Headey, S.J.,Rhodes, D.I.,Mulder, R.J.,Dolezal, O.,Deadman, J.J.,Newman, J.,Chalmers, D.K.,Parker, M.W.,Peat, T.S.,Scanlon, M.J.
Parallel Screening of Low Molecular Weight Fragment Libraries: Do Differences in Methodology Affect Hit Identification?
J.Biomol.Screen, 18:147-, 2013

PubMed Abstract: Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed a fragment screening campaign on the HIV-1 integrase core domain (IN) using similar commercially purchased fragment libraries. The two campaigns used different screening methods for the preliminary identification of fragment hits; one used saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), and the other used surface plasmon resonance (SPR) spectroscopy. Both initial screens were followed by X-ray crystallography. Using the STD-NMR/X-ray approach, 15 IN/fragment complexes were identified, whereas the SPR/X-ray approach found 6 complexes. In this article, we compare the approaches that were taken by each group and the results obtained, and we look at what factors could potentially influence the final results. We find that despite using different approaches with little overlap of initial hits, both approaches identified binding sites on IN that provided a basis for fragment-based lead discovery and further lead development. Comparison of hits identified in the two studies highlights a key role for both the conditions under which fragment binding is measured and the criteria selected to classify hits.

PubMed: 23139382
DOI: 10.1177/1087057112465979

Experimental method

X-RAY DIFFRACTION (1.8 Å)