In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3

Callejo, Gerard; Pattison, Luke A.; Greenhalgh, Jack; Chakrabarti, Sampurna; Andreopoulou, Evangelia; Hockley, James R.F.; Smith, Ewan St. John; Rahman, Taufiq

doi:10.1016/j.bcp.2020.113834

Cited by 13 publications

(15 citation statements)

References 72 publications

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“…The first of these to be identified was 2-guanidine-4-methylquinazoline (GMQ, Figure 7a ), a small, nitrogen-rich compound, which activates homomeric rASIC3 at 100 µM at neutral pH 7.4 by binding to the non-proton ligand sensing domain encompassing Glu79 and Glu423 [ 191 ]. GMQ has an EC 50 of 680 µM (in rASIC3 at pH 7.4), compounds with related structures guanabenz and sephin1 having an EC 50 for activation at neutral pH of 67.5 µM and 1220 µM, respectively; in addition, GMQ and guanabenz enhanced transient and sustained phases of acid-activation of ASIC3 [ 192 ]. Another guanidine-based compound is 4-chlorophenylguanidine (4-CPG, Figure 7b ), which has been shown to increase the ASIC3 half-maximal pH activation from 6.79 to 7.12; but only at a very high concentration of 1 mM [ 193 ].…”

Section: Modulation Of Asic3mentioning

confidence: 99%

Acid-sensing ion channel 3: An analgesic target

2021

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Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily. It consists of one of 7 different ASIC subunits encoded by 5 different genes. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo-and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC3 can encode prolonged acidosis as a nociceptive signal. Furthermore, certain mediators sensitise ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions.

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Section: Modulation Of Asic3mentioning

confidence: 99%

Acid-sensing ion channel 3: An analgesic target

2021

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“…A screen of 339,240 molecules from the ChemDiv Diversity ® , MayBridge Hit Locator ® , and Enamine Hit Locator ® chemical libraries in Rapid Overlay of Chemical Structures (ROCS) (OpenEye Scientific Software, Santa Fe, NM, USA) [ 63 , 64 ] and subsequent electrostatic field comparison in Forge (Cresset, Litlington, Cambridgeshire) [ 65 , 66 , 67 ], revealed 24 similar hits to the reference ligand, GRL-0617 (Supporting Information, Figure S1 ), which were commercially available (Supporting Information, Table S1 ). Of these hits, 18 had a Shape Tanimoto score (denoting structural/3D shape similarity to the reference) above 0.8 (Supporting Information, Figure S2 ), with the highest being that of the hit with PubChem Compound ID (CID) 121589399 ( Figure 2 a).…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, four compounds ( Figure 3 b–e; Supporting Information, Figure S3 ), including 121589399 obtained field scores (denoting electrostatic similarity to reference) above 0.8. Hits with field scores of 0.8 and above have a strong potential to be bioactive [ 67 ].…”

Section: Resultsmentioning

confidence: 99%

“…Blind docking [ 67 , 68 ] of the reference ligand GRL-0617 against PL pro in several programs showed that AutoDock Vina [ 69 ] could best reproduce the co-crystallised GRL-0617 pose, as shown in Figure 4 . When the docked pose was superimposed against the co-crystallised pose, there was found to be a root-mean-square-deviation (RMSD) of ~0.4 Å (within the ≤2 Å acceptable range for validation of self-docking).…”

Section: Resultsmentioning

confidence: 99%

“…In the ligand-based work, compound 121589399 had notably obtained the best Shape Tanimoto score, and a field score of above 0.8, and as well as the most favourable predicted free energy of binding in the initial blind docking. ROCS and Forge have previously been demonstrated to yield bioactive ligands [ 67 , 94 ]. Before blind docking, we first tested several programs to find out which would reproduce the co-crystallised GRL-0617 pose with the lowest RMSD between docked and co-crystallised pose, in which AutoDock Vina outperformed the other programs.…”

Section: Discussionmentioning

confidence: 99%

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Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

2021

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The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.

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Rational design of allosteric modulators: Challenges and successes

Chatzigoulas

Cournia

2021

WIREs Comput Mol Sci

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Recent advances in structural biology and computational techniques have revealed allosteric mechanisms for an abundance of targets leading to the establishment of rational design of allosteric modulators as a new avenue for drug discovery. Considering that allostery is an intrinsic property of the protein conformational ensemble, allosteric drug design has the potential to develop into an innovative approach to modulate the dysregulation of therapeutic targets that are considered to be undruggable at their orthosteric site, explore strategic design opportunities to tackle new chemical space, or develop mutant-specific therapies to target mutations occurring far from the enzyme active site. Traditionally, allosteric drug discovery has been performed through high-throughput screening or through serendipitous discoveries; however, recent developments in structure-based and ligand-based methods have led to exciting advancements of designing bioactive allosteric ligands rationally. In this review article, we highlight the advantages and disadvantages of allosteric modulators and present structure-based and ligand-based drug design methodologies for the identification of allosteric binding sites and allosteric modulators. We also illustrate representative studies for allosteric modulators design for proteins belonging to a wide range of protein families, also considering irreversible binding with covalent allosteric modulators. Additionally, we analyze challenges and successes in the rational design of allosteric inhibitors and activators. Finally, we present the future of rational allosteric ligand design with newly built computational tools that we expect to be applied in future studies, concluding to theoretical and practical guidelines for allosteric ligand design strategies and identify knowledge gaps that need to be addressed to improve efficiency in allosteric drug design.

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In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3

Cited by 13 publications

References 72 publications

Acid-sensing ion channel 3: An analgesic target

Acid-sensing ion channel 3: An analgesic target

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

Rational design of allosteric modulators: Challenges and successes

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