Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

Abstract

Allostery is a fundamental and extensive mechanism of intramolecular signal transmission. Allosteric drugs possess several unique pharmacological advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity. However, owing to the complexity of allosteric regulation, experimental approaches for the development of allosteric modulators are traditionally serendipitous. Recently, the reversed allosteric communication theory has been proposed, providing a feasible tool for the unbiased detection of allosteric sites. Herein, we review the latest research on the reversed allosteric communication effect using the examples of sirtuin 6, epidermal growth factor receptor, 3-phosphoinositide-dependent protein kinase 1, and Related to A and C kinases (RAC) serine/threonine protein kinase B and recapitulate the methodologies of reversed allosteric communication strategy. The novel reversed allosteric communication strategy greatly expands the horizon of allosteric site identification and allosteric mechanism exploration and is expected to accelerate an end-to-end framework for drug discovery.

Elucidation of the conformational dynamics and assembly of Argonaute–RNA complexes by distinct yet coordinated actions of the supplementary microRNA

“…Molecular dynamics (MD) simulations that explore protein and nucleic acid conformational dynamics at the atomic level are critical for understanding of target repression and TDMD process [37] , [38] , [39] , [40] , [41] , [42] , [43] . In the recent work, we have used MD simulations to directly uncover biomolecular mechanisms and protein–ligand/protein or protein–DNA/RNA recognitions [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] . Previous investigations on AGO utilizing large-scale MD simulations have successfully illuminated detailed mechanisms behind AGO-RNA interaction [58] , [59] , [60] and have been testified by experiments [61] .…”

CDK9 inhibitors in cancer research

“…155 As above, ATP-competitive inhibitors formed one to three hydrogen bonds to the amino acids situated in the hinge region of the target kinase, similar to the binding mode of the adenine residue of the ATP. 156 Allosteric inhibitors induced a conformational change to the kinase and modified its activity. 157,158 Recently, several allosteric inhibitors for other protein kinases have been developed and reported with advantages of high selectivity and few adverse effects.…”

Delineating the conformational landscape and intrinsic properties of the angiotensin II type 2 receptor using a computational study

“…In addition, the P6 site tends to be an allosteric one since classical downstream proteins bound here do not interact with AT 2 R [8] , [79] , [80] . Hence, regulators targeting P6 may show greater selectivity and less toxicity as the common advantage for allosteric modulators [81] , [82] , [83] , [84] , [85] , [86] . Notably, the result of virtual screening are shown for possible ligand binding mode for P6 but their bioactivity was not confirmed by experiments.…”