Improved Method for the Identification and Validation of Allosteric Sites

Song, Kun; Liu, Xinyi; Huang, Wenkang; Lu, Shaoyong; Shen, Qiancheng; Zhang, Lu; Zhang, Jian

doi:10.1021/acs.jcim.7b00014

Cited by 100 publications

(109 citation statements)

References 30 publications

(44 reference statements)

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“…Serious attempts to utilize the advantages of targeting allosteric sites instead of the orthosteric ones have only started in recent years, and the concept of allosteric drugs has since formed an important part in drug discovery [ 1 , 2 , 5 , 6 ]. Prediction of allosteric sites that can remotely regulate the dynamics at the functional site of interest has been shown to be a challenging task [ 5 , 15 , 16 ]. In this paper we test the hypothesis of the reversibility of allosteric communication, according to which the perturbation at the functional site results in a signal that propagates towards allosterically active protein regions.…”

Section: Discussionmentioning

confidence: 99%

“…One of the major hurdles in the development of allosteric drugs lies in the finding of allosteric sites [ 5 , 15 – 17 ], for which a repertoire of experimental and computational methods is being developed. High-throughput fragment-based screening using a large chemical library formed the main thrust in the identification of potential allosteric sites and lead compounds in pharmaceutical research [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response

2018

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The omnipresence of allosteric regulation together with the fundamental role of structural dynamics in this phenomenon have initiated a great interest to the detection of regulatory exosites and design of corresponding effectors. However, despite a general consensus on the key role of dynamics most of the earlier efforts on the prediction of allosteric sites are heavily crippled by the static nature of the underlying methods, which are either structure-based approaches seeking for deep surface pockets typical for “traditional” orthosteric drugs or sequence-based techniques exploiting the conservation of protein sequences. Because of the critical role of global protein dynamics in allosteric signaling, we investigate the hypothesis of reversibility in allosteric communication, according to which allosteric sites can be detected via the perturbation of the functional sites. The reversibility is tested here using our structure-based perturbation model of allostery, which allows one to analyze the causality and energetics of allosteric communication. We validate the “reverse perturbation” hypothesis and its predictive power on a set of classical allosteric proteins, then, on the independent extended benchmark set. We also show that, in addition to known allosteric sites, the perturbation of the functional sites unravels rather extended protein regions, which can host latent regulatory exosites. These protein parts that are dynamically coupled with functional sites can also be used for inducing and tuning allosteric communication, and an exhaustive exploration of the per-residue contributions to allosteric effects can eventually lead to the optimal modulation of protein activity. The site-effector interactions necessary for a specific mode and level of allosteric communication can be fine-tuned by adjusting the site’s structure to an available effector molecule and by the design or selection of an appropriate ligand.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response

2018

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“…Rapid progress in bioinformatics paves the avenue for computation‐aided allosteric drug discovery and expands the repertoire of druggable PPI targets. Various theoretical models have been put forward for computational allosteric site prediction tools, such as the structure‐based model in AlloSite, the Normal mode analysis‐based model in PARS and the topology‐based model in STRESS . In addition, very recent advances such as AlloSigMA, which provides a quantitative tool for analyzing the energetics underlying allosteric communication, and AlloFinder, which supplies allosterome analysis and virtual screening and scoring, may also be useful tools for allosteric target identification within PPI systems.…”

Section: Discussionmentioning

confidence: 99%

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Zhang

2019

Medicinal Research Reviews

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Protein‐protein interactions (PPIs) are closely implicated in various types of cellular activities and are thus pivotal to health and disease states. Given their fundamental roles in a wide range of biological processes, the modulation of PPIs has enormous potential in drug discovery. However, owing to the general properties of large, flat, and featureless interfaces of PPIs, previous attempts have demonstrated that the generation of therapeutic agents targeting PPI interfaces is challenging, rendering them almost “undruggable” for decades. To date, rapid progress in chemical and structural biology techniques has promoted the exploitation of allostery as a novel approach in drug discovery. By attaching to allosteric sites that are topologically and spatially distinct from PPI interfaces, allosteric modulators can achieve improved physiochemical properties. Thus, allosteric modulators may represent an alternative strategy to target intractable PPIs and have attracted intense pharmaceutical interest. In this review, we first briefly introduce the characteristics of PPIs and then present different approaches for investigating PPIs, as well as the latest methods for modulating PPIs. Importantly, we comprehensively review the recent progress in the development of allosteric modulators to inhibit or stabilize PPIs. Finally, we conclude with future perspectives on the discovery of allosteric PPI modulators, especially the application of computational methods to aid in allosteric PPI drug discovery.

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“…Allosteric effects are not easily detectable by any single method as they can take many forms, and a diverse pool of conformational samples is often needed to expose these rare events [41,[45][46][47]. Current understanding of the details of allosteric mechanisms is still fragmentary [48].…”

Section: Understanding Allosteric Mechanisms Using Existing Approachesmentioning

confidence: 99%

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

Amamuddy

Veldman

Manyumwa

et al. 2020

IJMS

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Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.

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Improved Method for the Identification and Validation of Allosteric Sites

Cited by 100 publications

References 30 publications

Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response

Reversing allosteric communication: From detecting allosteric sites to inducing and tuning targeted allosteric response

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

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