scholarly journals A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

2016 ◽  
Vol 12 ◽  
pp. 125-138 ◽  
Author(s):  
Steven C Zimmerman
Keyword(s):  
Small Molecules ◽  
Supramolecular Chemistry ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Early Life ◽  
Rational Design ◽  
Early Experience ◽  
Therapeutic Agents ◽  
Early Career ◽  
Molecular Tweezers

This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

scholarly journals Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

2019 ◽  
Vol 20 (16) ◽  
pp. 4017 ◽  
Author(s):  
Kaalak Reddy ◽  
Jana R. Jenquin ◽  
John D. Cleary ◽  
J. Andrew Berglund
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Disease Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Rna Toxicity ◽  
Complex Mechanisms ◽  
Potential Use

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).

scholarly journals Design of a small molecule against an oncogenic noncoding RNA

2016 ◽  
Vol 113 (21) ◽  
pp. 5898-5903 ◽  
Author(s):  
Sai Pradeep Velagapudi ◽  
Michael D. Cameron ◽  
Christopher L. Haga ◽  
Laura H. Rosenberg ◽  
Marie Lafitte ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecules ◽  
Cancer Cells ◽  
Small Molecule ◽  
Noncoding Rna ◽  
Breast Cancer Cells ◽  
Rational Design ◽  
Pharmacokinetic Profile ◽  
Tumor Burden

The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif–small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm.

scholarly journals How does a small molecule bind at a cryptic binding site?

2021 ◽  
Author(s):  
Yibing Shan ◽  
Venkatesh P. Mysore ◽  
Abba E. Leffler ◽  
Eric T. Kim ◽  
Shiori Sagawa ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Site ◽  
Small Molecule ◽  
Protein Interactions ◽  
Binding Sites ◽  
Rational Design ◽  
Structural Information ◽  
Interleukin 2 ◽  
Md Simulations ◽  
Drug Binding

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)—which performs its function by forming a PPI with its receptor—without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein–small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2–small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.

scholarly journals Molecular basis of small-molecule binding to α-synuclein

2021 ◽  
Author(s):  
Paul Robustelli ◽  
Alain Ibanez-de-Opakua ◽  
Cecily Campbell-Bezat ◽  
Fabrizio Giordanetto ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rational Design ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Structural Features ◽  
Atomic Level ◽  
Disordered Proteins ◽  
Structure Based Drug Design ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

scholarly journals Suprachoroidal Delivery of Small Molecules, Nanoparticles, Gene and Cell Therapies for Ocular Diseases

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 288
Author(s):  
Chen-rei Wan ◽  
Leroy Muya ◽  
Viral Kansara ◽  
Thomas A. Ciulla
Keyword(s):  
Drug Delivery ◽  
Gene Therapy ◽  
Small Molecules ◽  
Small Molecule ◽  
Viral Vector ◽  
Choroidal Melanoma ◽  
Therapeutic Agents ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Age Related

Suprachoroidal drug delivery technology has advanced rapidly and emerged as a promising administration route for a variety of therapeutic candidates, in order to target multiple ocular diseases, ranging from neovascular age-related macular degeneration to choroidal melanoma. This review summarizes the latest preclinical and clinical progress in suprachoroidal delivery of therapeutic agents, including small molecule suspensions, polymeric entrapped small molecules, gene therapy (viral and nonviral nanoparticles), viral nanoparticle conjugates (VNCs), and cell therapy. Formulation customization is critical in achieving favorable pharmacokinetics, and sustained drug release profiles have been repeatedly observed for multiple small molecule suspensions and polymeric formulations. Novel therapeutic agents such as viral and nonviral gene therapy, as well as VNCs, have demonstrated promise in animal studies. Several of these suprachoroidally-administered therapies have been assessed in clinical trials, including small molecule suspensions of triamcinolone acetonide and axitinib, viral vector RGX-314 for gene therapy, and VNC AU-011. With continued drug delivery research and optimization, coupled with customized drug formulations, suprachoroidal drug delivery may address large unmet therapeutic needs in ophthalmology, targeting affected tissues with novel therapies for efficacy benefits, compartmentalizing therapies away from unaffected tissues for safety benefits, and achieving durability to relieve the treatment burden noted with current agents.

scholarly journals Selective inhibition of MBNL1–CCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2) †

2011 ◽  
Vol 39 (20) ◽  
pp. 8881-8890 ◽  
Author(s):  
Chun-Ho Wong ◽  
Yuan Fu ◽  
Sreenivasa Rao Ramisetty ◽  
Anne M. Baranger ◽  
Steven C. Zimmerman
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Selective Inhibition ◽  
Therapeutic Agents ◽  
Myotonic Dystrophy Type ◽  
Myotonic Dystrophy Type 2

scholarly journals Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model

2019 ◽  
Vol 116 (16) ◽  
pp. 7799-7804 ◽  
Author(s):  
Alicia J. Angelbello ◽  
Suzanne G. Rzuczek ◽  
Kendra K. Mckee ◽  
Jonathan L. Chen ◽  
Hailey Olafson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Neuromuscular Disorder ◽  
Repeat Expansion ◽  
Rna Structures ◽  
Target Disease ◽  
Preclinical Animal Models

Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that recognizes the structure of r(CUG)exp and cleaves it in both DM1 patient-derived myotubes and a DM1 mouse model, leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects in vivo without detectable off-targets. Thus, small molecules that bind and cleave RNA have utility as lead chemical probes and medicines and can selectively target disease-causing RNA structures to broadly improve defects in preclinical animal models.

scholarly journals Active site plasticity and possible modes of chemical inhibition of the human DNA deaminase APOBEC3B

2019 ◽  
Author(s):  
Ke Shi ◽  
Özlem Demir ◽  
Michael A. Carpenter ◽  
Surajit Banerjee ◽  
Daniel A. Harki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Active Site ◽  
Rational Design ◽  
Catalytic Domain ◽  
Critical Role ◽  
Cytosine Deaminase ◽  
Zinc Ion ◽  
Tumor Evolution ◽  
Active Site Residues

AbstractThe single-stranded DNA cytosine deaminase APOBEC3B (A3B) functions in innate immunity against viruses, but is also strongly implicated in eliciting mutations in cancer genomes. Because of the critical role of A3B in promoting virus and tumor evolution, small molecule inhibitors are desirable. However, there is no reported structure for any of the APOBEC3-family enzymes in complex with a small molecule bound in the active site, which hampers the development of small molecules targeting A3B. Here we report high-resolution structures of an active A3B catalytic domain chimera with loop 7 residues exchanged with those from the corresponding region of APOBEC3G (A3G). The structures reveal novel open conformations lacking the catalytically essential zinc ion, with the highly conserved active site residues extensively rearranged. These inactive conformations are stabilized by 2-pyrimidone or an iodide ion bound in the active site. Molecular dynamics simulations corroborate the remarkable plasticity of the engineered active site and identify key interactions that stabilize the native A3B active site. These data provide insights into A3B active site dynamics and suggest possible modes of its inhibition by small molecules, which would aid in rational design of selective A3B inhibitors for constraining virus and tumor evolution.

In the Quest for a Stable Triplet State in Small Polyaromatic Hydrocarbons : An In-Silico Tool for Rational Design and Prediction

2019 ◽  
Author(s):  
Madhumita Rano ◽  
Sumanta K Ghosh ◽  
Debashree Ghosh
Keyword(s):  
Triplet State ◽  
Small Molecules ◽  
In Silico ◽  
Qualitative Agreement ◽  
Rational Design ◽  
Polyaromatic Hydrocarbons ◽  
Spin Hamiltonian ◽  
Spin Frustration ◽  
Computationally Efficient ◽  
High Level

<div>Combining the roles of spin frustration and geometry of odd and even numbered rings in polyaromatic hydrocarbons (PAHs), we design small molecules that show exceedingly small singlet-triplet gaps and stable triplet ground states. Furthermore, a computationally efficient protocol with a model spin Hamiltonian is shown to be capable of qualitative agreement with respect to high level multireference calculations and therefore, can be used for fast molecular discovery and screening.</div>

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