Allosteric Methods and Their Applications: Facilitating the Discovery of Allosteric Drugs and the Investigation of Allosteric Mechanisms

Abstract

CONSPECTUS: Allostery, or allosteric regulation, is the phenomenon in which protein functional activity is altered by the binding of an effector at an allosteric site that is topographically distinct from the orthosteric, active site. As one of the most direct and efficient ways to regulate protein function, allostery has played a fundamental role in innumerable biological processes of all living organisms, including enzyme catalysis, signal transduction, cell metabolism, and gene transcription. It is thus considered as "the second secret of life". The abnormality of allosteric communication networks between allosteric and orthosteric sites is associated with the pathogenesis of human diseases. Allosteric modulators, by attaching to structurally diverse allosteric sites, offer the potential for differential selectivity and improved safety compared with orthosteric drugs that bind to conserved orthosteric sites. Harnessing allostery has thus been regarded as a novel strategy for drug discovery. Despite much progress having been made in the repertoire of allostery since the turn of the millennium, the identification of allosteric drugs for therapeutic targets and the elucidation of allosteric mechanisms still present substantial challenges. These challenges are derived from the difficulties in the identification of allosteric sites and mutations, the assessment of allosteric protein−modulator interactions, the screening of allosteric modulators, and the elucidation of allosteric mechanisms in biological systems. To address these issues, we have developed a panel of allosteric services for specific allosteric applications over the past decade, including (i) the creation of the Allosteric Database, with the aim of providing comprehensive allosteric information such as allosteric proteins, modulators, sites, pathways, etc., (ii) the construction of the ASBench benchmark of high-quality allosteric sites for the development of computational methods for predicting allosteric sites, (iii) the development of Allosite and AllositePro for the prediction of the location of allosteric sites in proteins, (iv) the development of the Alloscore scoring function for the evaluation of allosteric protein−modulator interactions, (v) the development of Allosterome for evolutionary analysis of query allosteric sites/modulators within the human proteome, (vi) the development of AlloDriver for the prediction of allosteric mutagenesis, and (vii) the development of AlloFinder for the virtual screening of allosteric modulators and the investigation of allosteric mechanisms. Importantly, we have validated computationally predicted allosteric sites, mutations, and modulators in the real cases of sirtuin 6, casein kinase 2α, phosphodiesterase 10A, and signal transduction and activation of transcription 3. Furthermore, our developed allosteric methods have been widely exploited by other users around the world for allosteric research. Therefore, these allosteric services are expected to expedite the discovery of allosteric drugs and the investiga...

Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

“…The small molecule PPIs modulators can interact not only with protein-protein interface but also with allosteric sites 55,56 (Fig. 1).…”

Identify old drugs as selective bacterial β‐GUS inhibitors by structural‐based virtual screening and bio‐evaluations

“…However, the Δ G pred value is comparable to its analogue Amox (Kong et al, ). The relative rigid molecule structures with fewer flexible bonds in N ‐Des and Amox introduce less entropy loss upon the binding, and the omission of entropy term may lead to the underestimation of binding free energy for this kind of molecules (Chen et al, ; Hou, Wang, Li, & Wang, ; Hou, Wang, Li, & Wang, ; Huang et al, ; Jiang et al, ; Lu, Shen, & Zhang, ; Sun et al, ; Sun, Li, Shen, et al, ; Sun, Li, Tian, Xu, & Hou, ; Wang et al, ; Xu, Sun, Li, Wang, & Hou, ). The non‐polar energy contributions (Δ E vdw + Δ G SA ) are the primary favorable terms in the binding free energy and determine the binding affinities of the studied compounds (Table ).…”

Autoinhibition can identify rare driver mutations and advise pharmacology

“…5,6,72,136,137 This shift should not necessarily retain, or restore, the autoinhibited state; it may adopt an alternative inactive state. Pharmacological success may reflect several factors, including (i) the relative differences in the stabilities between the active and autoinhibited states; (ii) the heights of the barrier between them.…”

“…If surmountable, the difference in stabilities is the paramount factor; and (iii) the ability of the drug to promote a shift of the free energy landscape, a hallmark of allosteric drugs. 5,6,72,136,137 This shift should not necessarily retain, or restore, the autoinhibited state; it may adopt an alternative inactive state.…”