scholarly journals Computational Improvement of Small-Molecule Inhibitors of Bacillus anthracis Protective Antigen Activation through Isostere-Based Substitutions

2019 ◽  
Author(s):  
Sandra V. R. L. Silva ◽  
Pedro J. Silva
Keyword(s):  
Bacillus Anthracis ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Protective Antigen ◽  
Binding Modes ◽  
Lead Compounds ◽  
Computational Work ◽  
Binding Cavity ◽  
The Stability ◽  
Dynamics Simulations

There has recently been interest in the development of small-molecule inhibitors of the oligomerization of Bacillus anthracis protective antigen for therapeutic use. Some of the proposed lead compounds have, however, unfavorable solubility in aqueous medium, which prevents their clinical use. In this computational work, we have designed several hundreds of derivatives with progressively higher hydrosolubility and tested their ability to dock the relevant binding cavity. The highest-ranking docking hits were then subjected to 125 ns-long simulations to ascertain the stability of the binding modes. Several of the potential candidates performed quite disappointingly , but two molecules showed very stable binding modes throughout the complete simulations. Besides the identification of these two promising leads, these molecular dynamics simulations allowed the discovery of several insights that shall prove useful in the further improvement of these candidate towards higher potency and stability.

scholarly journals Small Molecule Inhibitors of Bacillus anthracis Protective Antigen Proteolytic Activation and Oligomerization

2012 ◽  
Vol 55 (18) ◽  
pp. 7998-8006 ◽  
Author(s):  
Alexander N. Wein ◽  
Brian N. Williams ◽  
Shihui Liu ◽  
Boris Ermolinsky ◽  
Daniele Provenzano ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Protective Antigen ◽  
Proteolytic Activation

Binding Modes of Small‐Molecule Inhibitors to the EED Pocket of PRC2

ChemPhysChem ◽  
2020 ◽  
Vol 21 (3) ◽  
pp. 263-271 ◽  
Author(s):  
Dading Huang ◽  
Shuaizhen Tian ◽  
Yifei Qi ◽  
John Z. H. Zhang
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Binding Modes

scholarly journals Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Alejandro Gil L. ◽  
Pedro A. Valiente ◽  
Pedro G. Pascutti ◽  
Tirso Pons
Keyword(s):  
Structure Function ◽  
Free Energy Calculations ◽  
Special Focus ◽  
Binding Modes ◽  
Linear Interaction ◽  
Lead Compounds ◽  
Structure Function Relationship ◽  
Function Relationship ◽  
Dynamics Simulations ◽  
Selection Of

The development of efficient and selective antimalariais remains a challenge for the pharmaceutical industry. The aspartic proteases plasmepsins, whose inhibition leads to parasite death, are classified as targets for the design of potent drugs. Combinatorial synthesis is currently being used to generate inhibitor libraries for these enzymes, and together with computational methodologies have been demonstrated capable for the selection of lead compounds. The high structural flexibility of plasmepsins, revealed by their X-ray structures and molecular dynamics simulations, made even more complicated the prediction of putative binding modes, and therefore, the use of common computational tools, like docking and free-energy calculations. In this review, we revised the computational strategies utilized so far, for the structure-function relationship studies concerning the plasmepsin family, with special focus on the recent advances in the improvement of the linear interaction estimation (LIE) method, which is one of the most successful methodologies in the evaluation of plasmepsin-inhibitor binding affinity.

Development of Small Molecule Inhibitors of the AML1-ETO and CBFβ-SMMHC Oncoproteins.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1591-1591
Author(s):  
Jolanta E. Grembecka ◽  
Kristin Graf ◽  
Yali Kong ◽  
Michael Douvas ◽  
Tomasz Cierpicki ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Cell Line ◽  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitors ◽  
Leukemia Cell Line ◽  
Runt Domain ◽  
Protein Protein Interaction ◽  
Lead Compounds ◽  
Binding Interface

Abstract Core binding factor (CBF) is a heterodimeric transcription factor composed of RUNX1 (CBFα) and CBFβ subunits which are essential for normal blood cell development. CBFβ functions to increase the DNA-binding of the RUNX1 subunit 20–40 fold and to protect the RUNX1 subunit against ubiqitination and proteasome degradation, making this protein-protein interaction critical for CBF function. Two of the most common translocations involving the subunits of CBF are the inv(16) and the t(8;21) which produce the chimeric proteins CBFβ-SMMHC and AML1-ETO, respectively, which are associated with the development of Acute Myeloid Leukemia (AML). The AML1-ETO fusion protein is a dominant inhibitor of wildtype RUNX1-CBFβ activity in vivo and causes a blockage in normal hematopoiesis, predisposing for the development of leukemia. The interaction between CBFβ and AML1-ETO is critical for its function, therefore treatments targeting AML1-ETO and blocking its interaction with CBFβ are highly likely to be therapeutically beneficial. The CBFβ-SMMHC fusion protein causes dysregulation of CBF function by means of anomalously tight binding to RUNX1. Since binding to RUNX1 is required for the dysfunction associated with CBFβ-SMMHC, this interaction represents an excellent target for inhibition as a potential therapeutic strategy. We have initiated efforts to develop small molecule inhibitors of the RUNX1-CBFβ interaction as possible therapeutics for the treatment of the associated leukemias. Both virtual screening searches, focused on the X-ray structures of RUNX1 Runt domain and CBFβ, and high-throughput screening of NCI (National Cancer Institute) and Maybridge fragment libraries were used to identify initial lead compounds interacting with these proteins and blocking heterodimerization of CBF. Compounds were tested experimentally by FRET (Fluorescence Resonance Energy Transfer) and ELISA for their inhibition of RUNX1-CBFβ interaction. This resulted in a number of initial lead compounds targeting either the Runt domain or CBFβ and inhibiting this protein-protein interaction. Based on the docking mode selected lead compounds were further optimized using medicinal chemistry approaches to increase their affinity and determine the structure-activity relationships (SAR). This resulted in several compounds with low micromolar affinity (IC50 < 10 μM) which effectively block the heterodimerization of CBF in vitro and in a cell-based assay. Interestingly, compounds targeting CBFβ bind to a site displaced from the binding interface for RUNX1 as shown by the NMR-based docking, i.e. these compounds function as allosteric inhibitors of this protein-protein interaction. The most potent compounds were tested either in the Kasumi-1 leukemia cell line harboring t(8;21) translocation or in the ME-1 cell line with inv(16), resulting in a blockage of proliferation, induction of apoptosis and differentiation of these cells. These compounds represent the first small molecule inhibitors targeting CBF and inhibiting this interaction. They represent good starting points for the development of therapeutically useful inhibitors. Several approaches are being explored to modify these compounds to achieve selectivity towards AML1-ETO or CBFβ-SMMHC oncoproteins versus wild type proteins.

scholarly journals Probing Binding Modes of Small Molecule Inhibitors to the Polo-Box Domain of Human Polo-like Kinase 1

2010 ◽  
Vol 1 (3) ◽  
pp. 110-114 ◽  
Author(s):  
Chenzhong Liao ◽  
Jung-Eun Park ◽  
Jeong K. Bang ◽  
Marc C. Nicklaus ◽  
Kyung S. Lee
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Binding Modes

scholarly journals Small-Molecule Inhibitors of Lethal Factor Protease Activity Protect against Anthrax Infection

2013 ◽  
Vol 57 (9) ◽  
pp. 4139-4145 ◽  
Author(s):  
Mahtab Moayeri ◽  
Devorah Crown ◽  
Guan-Sheng Jiao ◽  
Seongjin Kim ◽  
Alan Johnson ◽  
...  
Keyword(s):  
Small Molecule ◽  
Neutralizing Antibodies ◽  
Small Molecule Inhibitors ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Similar Efficacy ◽  
Content Type ◽  
Edema Factor ◽  
Anthrax Infection

ABSTRACTBacillus anthracis, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. The bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. We previously developed small-molecule inhibitors of lethal factor proteolytic activity (LFIs) and demonstrated theirin vivoefficacy in a rat lethal toxin challenge model. In this work, we show that these LFIs protect against lethality caused by anthrax infection in mice when combined with subprotective doses of either antibiotics or neutralizing monoclonal antibodies that target edema factor. Significantly, these inhibitors provided protection against lethal infection when administered as a monotherapy. As little as two doses (10 mg/kg) administered at 2 h and 8 h after spore infection was sufficient to provide a significant survival benefit in infected mice. Administration of LFIs early in the infection was found to inhibit dissemination of vegetative bacteria to the organs in the first 32 h following infection. In addition, neutralizing antibodies against edema factor also inhibited bacterial dissemination with similar efficacy. Together, our findings confirm the important roles that both anthrax toxins play in establishing anthrax infection and demonstrate the potential for small-molecule therapeutics targeting these proteins.

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