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Two Methods, One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses.

ABSTRACT: In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein-ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Particularly for flexible proteins, such as kinases, and larger ligands cocrystallization captures more reliable the correct binding pose and induced protein adaptations. The geometrical discrepancies between soaking and cocrystallization appear smaller for fragment-sized ligands. For larger flexible ligands that trigger conformational changes of the protein, soaking can be misleading and underestimates the number of possible polar interactions due to inadequate, highly impaired positions of protein amino-acid side and main chain atoms. Thus, if applicable cocrystallization should be the gold standard to study protein-ligand complexes.

SUBMITTER: Wienen-Schmidt B

PROVIDER: S-EPMC7821316 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Two Methods, One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses.

Wienen-Schmidt Barbara B Oebbeke Matthias M Ngo Khang K Heine Andreas A Klebe Gerhard G

ChemMedChem 20201030 1

In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein-ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Part ...[more]

PMID: 33029876

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Project description:BackgroundCopro-parasitological diagnosis is still a challenge in management of helminth infections at individual and community levels in resource-limited settings.The aim of our study was to compare the performance of three quantitative techniques: Kato-Katz, McMaster and Mini-FLOTAC methids. The study was carried out in Oran, Northern Argentina.Methods200 schoolchildren were enrolled to provide a single stool sample, which was tested for helminth infections with Kato-Katz, McMaster and Mini-FLOTAC methods. The Mini-FLOTAC was performed with two flotation solutions (FS2 saturated saline and FS7 zinc sulphate). Preparation and reading time for each of the three methods was calculated both when processing single and multiple samples.ResultsOut of 193 schoolchildren examined, 40% were positive for any helminth infection by any method; the most prevalent was Hymenolepis nana (23%) followed by Ascaris lumbricoides (17%) and a third group of less prevalent helminths: Enterobius vermicularis, Trichuris trichiura and hookworms (11% all together). Mini-FLOTAC FS2 was more sensitive than FS7 for H. nana (93% vs 78%) and for other helminths (85% vs 80%), whereas FS7 was more sensitive for A. lumbricoides (87% vs 61%). Kato-Katz method was more sensitive than McMaster method for A. lumbricoides (84% vs 48%) and for other helminths (48% vs 43%) except for H. nana (49% vs 61%). As for egg counts, Mini-FLOTAC FS2 reported 904 eggs per gram of faeces (EPG) for H. nana (vs 457 with McMaster and 111 with Kato-Katz) and 1177 EPG for A. lumbricoides (vs 1315 with Kato-Katz and 995 with McMaster); FS2 detected the highest EPG for both H.nana and A.lumbricoides (904 vs 568 and 1177 vs 643 respectively), the differences were not statistically significant. The technique feasibility was calculated: Kato-Katz mean time was 48 minutes/sample, Mini-FLOTAC 13 minutes/sample and McMaster 7 minutes/sample. However, especially for Kato-Katz and Mini-FLOTAC, the mean time (min/sample) decreased significantly when processing multiple samples.ConclusionsMini-FLOTAC is a promising technique for helminth diagnosis, it is more sensitive than Kato-Katz and McMaster for H. nana and as sensitive as Kato-Katz and more sensitive than McMaster for A. lumbricoides identification. Egg counts differences although relevant, did not reach statistical significance.

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Two Methods, One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses.

Publications

Two Methods, One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses.

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