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Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions.

ABSTRACT: Discovery of novel tool compounds and drug leads against a range of unorthodox protein targets has pushed both experimental screening methodologies as well as the field of structure-based design to the limit in recent years. Increasingly, it has been recognized that some of the most desirable targets for the development of small-molecule effectors are actually protein-protein and protein-nucleic acid interactions. There are numerous nontrivial challenges to pursuing small-molecule lead compounds directed toward PPIs and PNIs: relatively shallow cavities, large surface areas that are natively complexed to macromolecules, complex patterns of interstitial waters, a paucity of "hot spots," large conformational changes upon ligand binding, etc. Although there have been some notable successes targeting PPIs in the last decade, there has been distinctly less success in the realm of targeting PNIs. This chapter focuses on an approach, successfully applied by our group to address the challenge of gaining traction on the PPI target RAD52, which is a protein that binds both single-stranded and double-stranded DNA, and is an anticancer target for certain types of cancer. There are many approaches to tackling the difficult problems of finding effective small molecules that disrupt PPIs and PNIs, but the methods presented here offer a series of elegant solutions, which integrate experimental HTS, biophysical methods, docking, and molecular dynamics in a powerful way. Additionally, the structural knowledge gained from these studies provides a means for rationally understanding what features lead to ligand affinity in these fascinating and highly unorthodox pockets.

SUBMITTER: Li Q

PROVIDER: S-EPMC6010167 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions.

Li Quinn Q Folly da Silva Constantino Laura L Spies M Ashley MA

Methods in enzymology 20180228

Discovery of novel tool compounds and drug leads against a range of unorthodox protein targets has pushed both experimental screening methodologies as well as the field of structure-based design to the limit in recent years. Increasingly, it has been recognized that some of the most desirable targets for the development of small-molecule effectors are actually protein-protein and protein-nucleic acid interactions. There are numerous nontrivial challenges to pursuing small-molecule lead compounds ...[more]

PMID: 29523234

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Project description:Molecular association of proteins with nucleic acids is required for many biological processes essential to life. Electrostatic interactions via ion pairs (salt bridges) of nucleic acid phosphates and protein side chains are crucial for proteins to bind to DNA or RNA. Counterions around the macromolecules are also key constituents for the thermodynamics of protein-nucleic acid association. Until recently, there had been only a limited amount of experiment-based information about how ions and ionic moieties behave in biological macromolecular processes. In the past decade, there has been significant progress in quantitative experimental research on ionic interactions with nucleic acids and their complexes with proteins. The highly negatively charged surfaces of DNA and RNA electrostatically attract and condense cations, creating a zone called the ion atmosphere. Recent experimental studies were able to examine and validate theoretical models on ions and their mobility and interactions with macromolecules. The ionic interactions are highly dynamic. The counterions rapidly diffuse within the ion atmosphere. Some of the ions are released from the ion atmosphere when proteins bind to nucleic acids, balancing the charge via intermolecular ion pairs of positively charged side chains and negatively charged backbone phosphates. Previously, the release of counterions had been implicated indirectly by the salt-concentration dependence of the association constant.Recently, direct detection of counterion release by NMR spectroscopy has become possible and enabled more accurate and quantitative analysis of the counterion release and its entropic impact on the thermodynamics of protein-nucleic acid association. Recent studies also revealed the dynamic nature of ion pairs of protein side chains and nucleic acid phosphates. These ion pairs undergo transitions between two major states. In one of the major states, the cation and the anion are in direct contact and form hydrogen bonds. In the other major state, the cation and the anion are separated by water. Transitions between these states rapidly occur on a picosecond to nanosecond time scale. When proteins interact with nucleic acids, interfacial arginine (Arg) and lysine (Lys) side chains exhibit considerably different behaviors. Arg side chains show a higher propensity to form rigid contacts with nucleotide bases, whereas Lys side chains tend to be more mobile at the molecular interfaces. The dynamic ionic interactions may facilitate adaptive molecular recognition and play both thermodynamic and kinetic roles in protein-nucleic acid interactions.

Dataset Information

Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions.

Publications

Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions.

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