Allosterism and Drug Discovery
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Abstract Interest in allostery and drug development has significantly expanded with increasingly broad ranges of targets and diseases. Experimental and computational approaches have led to advances in understanding of the mechanisms and roles of protein dynamics and conformational states, and come together in the concept of conformational selection. The models of Monod, Wyman, and Changeux and Koshland, Nemethy, and Filmer provide conceptual explanations of homotropic cooperativity and heterotropic allostery, while conformational selection provides realistic detail that can be exploited in drug design. Distinction between allostery and cooperativity and development of approaches to identify cryptic sites on proteins significantly expands the range of targets for allosteric drug design. High‐throughput screening and SAR optimization remain a staple of drug design, however, increased understanding of the thermodynamics of protein–ligand interactions and conformational changes, and the mechanisms of information flow between existing allosteric sites and across subunit interfaces or between allosteric and active sites, rational design of ligands to interact with a cryptic “allosteric” site on any protein becomes possible. Recent “omics” approaches to identify druggable targets both genome wide and in vivo further enhance the range of targets for drug design, both covalent and noncovalent, exploiting allosteric and cooperative properties of proteins.Keywords:
Cooperativity
Druggability
Abstract Magnitude of cooperativity of a hypothetical m ‐subunit allosteric system of hemoglobin type is discussed, based on computation of the amount of O 2 to be transferred to the corresponding monomeric nonallosteric system of myoglobin type. For quantitative discussion, “allosteric gain” is defined as the difference between the amount of O 2 to be transferred from the allosteric to the nonallosteric system and that from the hypothetical system of average O 2 affinity to the nonallosteric system. These two quantities, allosteric gain and amount of O 2 transfer, are quite sensitive to equilibrium constant ratio, especially K m /K 1 , ( K i+1 / K i ) max , and i. Hill's coefficient appropriately describes neither the amount of O 2 transferred nor allosteric gain. Allosteric gain or the amount of O 2 transfer which is best characterized by the total cooperativity index ( K m /K 1 ) and the local cooperativity indices ( K i+1 /K i ) seem to be appropriate measures of the magnitude of cooperativity.
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Allosteric enzyme
Cooperative binding
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Abstract: The current pandemic caused by the COVID-19 disease has reached everywhere in the world and has affected every aspect of our lives. As of the current data, the World Health Organization (WHO) has reported more than 300 million confirmed COVID-19 cases worldwide and more than 5 million deaths. M pro is an enzyme that plays a key role in the life cycle of the SARS-CoV-2 virus, and it is vital for the disease progression. The M pro enzyme seems to have several allosteric sites that can hinder the enzyme catalytic activity. Furthermore, some of these allosteric sites are located at or nearby the dimerization interface which is essential for the overall M pro activity. In this review paper, we investigate the potential of the M pro allosteric site to act as a drug target, especially since they interestingly appear to be resistant to mutation. The work is illustrated through three subsequent sections: First, the two main categories of M pro allosteric sites have been explained and discussed. Second, a total of six pockets have been studied and evaluated for their druggability and cavity characteristics. Third, the experimental and computational attempts for the discovery of new allosteric inhibitors have been illustrated and discussed. To sum up, this review paper gives a detailed insight into the feasibility of developing new M pro inhibitors to act as a potential treatment for the COVID-19 disease. Graphical Abstract: Keywords: COVID-19, M pro , SARS-CoV-2, allosteric sites, druggability, antiviral
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Coronavirus
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Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Using two structurally analogous subtype-specific allosteric inhibitors of P2X3, AF-353 and AF-219, the latter being a drug candidate under phase II clinical trials for refractory chronic cough and idiopathic pulmonary fibrosis, we defined the molecular interactions between the drugs and receptors and the mechanism by which allosteric changes in the LF, DF, and LB domains modulate ATP activation of P2X3. Our detailed characterization of this druggable allosteric site should inspire new strategies to develop P2X3-specific allosteric modulators for clinical use.
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Allosteric modulator
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The MEK1 kinase plays a critical role in key cellular processes, and as such, its dysfunction is strongly linked to several human diseases, particularly cancer. MEK1 has consequently received considerable attention as a drug target, and a significant number of small-molecule inhibitors of this kinase have been reported. The majority of these inhibitors target an allosteric pocket proximal to the ATP binding site which has proven to be highly druggable, with four allosteric MEK1 inhibitors approved to date. Despite the significant attention that the MEK1 allosteric site has received, chemotypes which have been shown structurally to bind to this site are limited. With the aim of discovering novel allosteric MEK1 inhibitors using a fragment-based approach, we report here a screening method which resulted in the discovery of multiple allosteric MEK1 binders, one series of which was optimized to sub-μM affinity for MEK1 with promising physicochemical and ADMET properties.
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Fragment (logic)
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A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C-region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations.
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Cooperative binding
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spike protein
Coronavirus
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Abstract The effects of activator molecule and repressive molecule on binding process between allosteric enzyme and substrate are discussed by considering the heterotropic effect of the regulating molecule that binds to allosteric enzyme. A model of allosteric enzyme with heterotropic effect is presented. The cooperativity and anticooperativity in the regulation process are studied.
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Allosteric enzyme
Cooperative binding
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Abstract Hemoglobin is the paradigm of cooperative protein-ligand binding. Cooperativity is the consequence of inter-subunit allosteric communication: binding at one site increases the affinity of the others. Despite half a century of studies, the mechanism behind oxygen binding in hemoglobin is not fully understood yet. In particular, it is not clear if cooperativity arises from preferential inter-subunit channels and which residues propagate the allosteric signal from one heme to the others. In this work, the heme-heme dynamical interactions have been mapped through a network-based analysis of residue conformational fluctuations, as described by molecular dynamics simulations. In particular, it was possible to suggest which inter-subunit interactions are mostly responsible of allosteric signalling and, within each pair of subunits, which protein fragments convey such signalling process.
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Cooperative binding
Allosteric enzyme
Protein Dynamics
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Summary Recent developments in the SARS-CoV-2 pandemic point to its inevitable transformation into an endemic disease, urging both diagnostics of emerging variants of concern (VOCs) and design of the variant-specific drugs in addition to vaccine adjustments. Exploring the structure and dynamics of the SARS-CoV-2 Spike protein, we argue that the high mutability characteristic of RNA viruses coupled with the remarkable flexibility and dynamics of viral proteins result in a substantial involvement of allosteric mechanisms. While allosteric effects of mutations should be considered in predictions and diagnostics of new VOCs, allosteric drugs advantageously avoid escaping mutations via non-competitive inhibition originating from many alternative distal locations. The exhaustive allosteric signalling and probing maps provide a comprehensive picture of allostery in the Spike protein, making it possible to locate sites of potential mutations that could work as new VOCs “drivers”, and to determine binding patches that may be targeted by newly developed allosteric drugs.
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spike protein
Protein Dynamics
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Druggability
Protein Dynamics
Allosteric modulator
Allosteric enzyme
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