Dataset Information

Decrypting a Cryptic Allosteric Pocket in H. pylori Glutamate Racemase.

ABSTRACT: One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target. In the current studies we present a successful way forward in rationally exploiting the cryptic allosteric pocket of H. pylori glutamate racemase, an essential enzyme in this pathogen's life cycle. A wide range of computational and experimental methods are employed in a workflow leading to the discovery of a series of natural product allosteric inhibitors which occupy the allosteric pocket of this essential racemase. The confluence of these studies reveals a fascinating source of the allosteric inhibition, which centers on the abolition of essential monomer-monomer coupled motion networks.

SUBMITTER: Chheda PR

PROVIDER: S-EPMC9169614 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Decrypting a Cryptic Allosteric Pocket in <i>H. pylori</i> Glutamate Racemase.

Chheda Pratik Rajesh PR Cooling Grant T GT Dean Sondra F SF Propp Jonah J Hobbs Kathryn F KF Spies M Ashley MA

Communications chemistry 20211210

One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target. In the current studies we present a successful way forward in rationally exploiting the cryptic allosteric pocket of <i ...[more]

PMID: 35673630

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Project description:Virtual screening is a widely used tool for drug discovery, but its predictive power can vary dramatically depending on how much structural data is available. In the best case, crystal structures of a ligand-bound protein can help find more potent ligands. However, virtual screens tend to be less predictive when only ligand-free crystal structures are available, and even less predictive if a homology model or other predicted structure must be used. Here, we explore the possibility that this situation can be improved by better accounting for protein dynamics, as simulations started from a single structure have a reasonable chance of sampling nearby structures that are more compatible with ligand binding. As a specific example, we consider the cancer drug target PPM1D/Wip1 phosphatase, a protein that lacks crystal structures. High-throughput screens have led to the discovery of several allosteric inhibitors of PPM1D, but their binding mode remains unknown. To enable further drug discovery efforts, we assessed the predictive power of an AlphaFold-predicted structure of PPM1D and a Markov state model (MSM) built from molecular dynamics simulations initiated from that structure. Our simulations reveal a cryptic pocket at the interface between two important structural elements, the flap and hinge regions. Using deep learning to predict the pose quality of each docked compound for the active site and cryptic pocket suggests that the inhibitors strongly prefer binding to the cryptic pocket, consistent with their allosteric effect. The predicted affinities for the dynamically uncovered cryptic pocket also recapitulate the relative potencies of the compounds (τb = 0.70) better than the predicted affinities for the static AlphaFold-predicted structure (τb = 0.42). Taken together, these results suggest that targeting the cryptic pocket is a good strategy for drugging PPM1D and, more generally, that conformations selected from simulation can improve virtual screening when limited structural data is available.

Project description:Cryptic species are a challenge for systematics, but their elucidation also may leave critical information gaps about the distribution, conservation status, and behavior of affected species. We use the leopard frogs of the eastern U.S. as a case study of this issue. We refined the known range of the recently described Rana kauffeldi, the Atlantic Coast Leopard Frog, relative to the region's two other leopard frog species, conducted assessments of conservation status, and improved methods for separating the three species using morphological field characters. We conducted over 2,000 call and visual surveys and took photographs of and tissue samples from hundreds of frogs. Genetic analysis supported a three-species taxonomy and provided determinations for 220 individual photographed frogs. Rana kauffeldi was confirmed in eight U.S. states, from North Carolina to southern Connecticut, hewing closely to the Atlantic Coastal Plain. It can be reliably differentiated in life from R. pipiens, and from R. sphenocephala 90% of the time, based on such characters as the femoral reticulum patterning, dorsal spot size and number, and presence of a snout spot. However, the only diagnostic character separating R. kauffeldi from R. sphenocephala remains the breeding call described in 2014. Based on our field study, museum specimens, and prior survey data, we suggest that R. kauffeldi has declined substantially in the northern part of its range, but is more secure in the core of its range. We also report, for the first time, apparent extirpations of R. pipiens from the southeastern portion of its range, previously overlooked because of confusion with R. kauffeldi. We conclude with a generalized ecological research agenda for cryptic species. For R. kauffeldi, needs include descriptions of earlier life stages, studies of niche partitioning with sympatric congeners and the potential for hybridization, and identification of conservation actions to prevent further declines.

Dataset Information

Decrypting a Cryptic Allosteric Pocket in H. pylori Glutamate Racemase.

Publications

Decrypting a Cryptic Allosteric Pocket in <i>H. pylori</i> Glutamate Racemase.

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