IDENTIFICATION OF A GENOMIC DRUG TARGET FOR KIDNEY INJURY AND THERAPEUTIC SCREENING OF NATURAL PRODUCTS DERIVED SMALL MOLECULES

Many natural compounds with interesting biomedical properties share one physicochemical property, namely a low water solubility. Polymer micelles are, among others, a popular means to solubilize hydrophobic compounds. The specific molecular interactions between the polymers and the hydrophobic drugs are diverse and recently it has been discussed that macromolecular engineering can be used to optimize drug loaded micelles. Specifically, π-π stacking between small molecules and polymers has been discussed as an important interaction that can be employed to increase drug loading and formulation stability. Here, we test this hypothesis using four different polymer amphiphiles with varying aromatic content and various natural products that also contain different relative amounts of aromatic moieties. While in the case of paclitaxel, having the lowest relative content of aromatic moieties, the drug loading decreases with increasing relative aromatic amount in the polymer, the drug loading of curcumin, having a much higher relative aromatic content, is increased. Interestingly, the loading using schizandrin A, a dibenzo[a,c]cyclooctadiene lignan with intermediate relative aromatic content is not influenced significantly by the aromatic content of the polymers employed. The very high drug loading, long term stability, the ability to form stable highly loaded binary coformulations in different drug combinations, small sized formulations and amorphous structures in all cases, corroborate earlier reports that poly(2-oxazoline) based micelles exhibit an extraordinarily high drug loading and are promising candidates for further biomedical applications. The presented results underline that the interaction between the polymers and the incorporated small molecules are complex and must be investigated in every specific case.<br>

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Alternative approaches to target Myc for cancer treatment

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00500-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Chen Wang ◽

Jiawei Zhang ◽

Jie Yin ◽

Yichao Gan ◽

Senlin Xu ◽

...

Keyword(s):

Cancer Treatment ◽

Small Molecules ◽

Drug Target ◽

The Past ◽

Physiological Processes ◽

Alternative Approaches ◽

Global Transcriptome ◽

Factor C ◽

Signaling Modules ◽

Druggable Targets

AbstractThe Myc proto-oncogene family consists of three members, C-MYC, MYCN, and MYCL, which encodes the transcription factor c-Myc (hereafter Myc), N-Myc, and L-Myc, respectively. Myc protein orchestrates diverse physiological processes, including cell proliferation, differentiation, survival, and apoptosis. Myc modulates about 15% of the global transcriptome, and its deregulation rewires the cellular signaling modules inside tumor cells, thereby acquiring selective advantages. The deregulation of Myc occurs in >70% of human cancers, and is related to poor prognosis; hence, hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades. Nevertheless, no specific drug is currently available to directly target Myc, mainly because of its “undruggable” properties: lack of enzymatic pocket for conventional small molecules to bind; inaccessibility for antibody due to the predominant nucleus localization of Myc. Although the topic of targeting Myc has actively been reviewed in the past decades, exciting new progresses in this field keep emerging. In this review, after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer, we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.

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Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions

Organic & Biomolecular Chemistry ◽

10.1039/d1ob00354b ◽

2021 ◽

Author(s):

Freideriki Michailidou ◽

Andrea Rentmeister

Keyword(s):

Natural Products ◽

Small Molecules ◽

Cascade Reactions ◽

Fine Tuning ◽

Wide Range

Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted...

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Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

RSC Advances ◽

10.1039/d0ra08769f ◽

2021 ◽

Vol 11 (4) ◽

pp. 2453-2461

Author(s):

Min-Che Tung ◽

Keng-Chang Tsai ◽

Kit-Man Fung ◽

Ming-Jaw Don ◽

Tien-Sheng Tseng

Keyword(s):

Natural Products ◽

Protein Kinase ◽

Tyrosine Kinase ◽

Mode Of Action ◽

Drug Target ◽

Receptor Protein ◽

Inflammatory Disorder ◽

Spleen Tyrosine Kinase ◽

Structure Activity Relationships ◽

Structure Activity

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.

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All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

10.1101/2021.02.08.430329 ◽

2021 ◽

Author(s):

Carolina Pérez Segura ◽

Boon Chong Goh ◽

Jodi A. Hadden-Perilla

Keyword(s):

Small Molecules ◽

Drug Target ◽

Structural Changes ◽

Salt Bridge ◽

Md Simulations ◽

Health Concern ◽

Protein Dimer ◽

B Virus ◽

Flexible Protein ◽

Dynamics Simulations

AbstractThe hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important anti-viral paradigm based on disrupting the timing of genome encapsulation. Crystallographic studies of AT130-bound complexes have been essential in explaining the effects of the small molecule on HBV capsid structure; however, computational examination reveals that key changes attributed to AT130 were erroneous, likely a consequence of interpreting poor resolution arising from a highly flexible protein. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that, rather than damaging spike helicity, AT130 enhances the capsid’s ability to recover it. A new conformational state is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these domains. Combined with dynamical network analysis, results describe a connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire capsid protein dimer.

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Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

10.1101/2020.12.16.422677 ◽

2020 ◽

Author(s):

Maria Kuzikov ◽

Elisa Costanzi ◽

Jeanette Reinshagen ◽

Francesca Esposito ◽

Laura Vangeel ◽

...

Keyword(s):

Enzymatic Activity ◽

Small Molecules ◽

Drug Target ◽

Treatment Options ◽

Cleavage Sites ◽

X Ray ◽

Binding Characteristics ◽

Main Protease ◽

Ic50 Values

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 uM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Angs., showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

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PROMISCUOUS 2.0: a resource for drug-repositioning

Nucleic Acids Research ◽

10.1093/nar/gkaa1061 ◽

2020 ◽

Vol 49 (D1) ◽

pp. D1373-D1380

Author(s):

Kathleen Gallo ◽

Andrean Goede ◽

Andreas Eckert ◽

Barbara Moahamed ◽

Robert Preissner ◽

...

Keyword(s):

Side Effects ◽

Small Molecules ◽

User Experience ◽

Drug Target ◽

Drug Repositioning ◽

Dynamic Network ◽

Structural Similarity ◽

New Drugs ◽

Entry Level ◽

Development Costs

Abstract The development of new drugs for diseases is a time-consuming, costly and risky process. In recent years, many drugs could be approved for other indications. This repurposing process allows to effectively reduce development costs, time and, ultimately, save patients’ lives. During the ongoing COVID-19 pandemic, drug repositioning has gained widespread attention as a fast opportunity to find potential treatments against the newly emerging disease. In order to expand this field to researchers with varying levels of experience, we made an effort to open it to all users (meaning novices as well as experts in cheminformatics) by significantly improving the entry-level user experience. The browsing functionality can be used as a global entry point to collect further information with regards to small molecules (∼1 million), side-effects (∼110 000) or drug-target interactions (∼3 million). The drug-repositioning tab for small molecules will also suggest possible drug-repositioning opportunities to the user by using structural similarity measurements for small molecules using two different approaches. Additionally, using information from the Promiscuous 2.0 Database, lists of candidate drugs for given indications were precomputed, including a section dedicated to potential treatments for COVID-19. All the information is interconnected by a dynamic network-based visualization to identify new indications for available compounds. Promiscuous 2.0 is unique in its functionality and is publicly available at http://bioinformatics.charite.de/promiscuous2.

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The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Molecules ◽

10.3390/molecules25030745 ◽

2020 ◽

Vol 25 (3) ◽

pp. 745 ◽

Cited By ~ 23

Author(s):

Beatriz G. de la Torre ◽

Fernando Albericio

Keyword(s):

Natural Products ◽

Pharmaceutical Industry ◽

Small Molecules ◽

Chemical Structure ◽

New Drugs ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

The Us ◽

New Chemical Entities ◽

Antibody Drug

During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

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Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications

Synthesis ◽

10.1055/s-0039-1690869 ◽

2020 ◽

Vol 52 (14) ◽

pp. 1991-2007 ◽

Cited By ~ 1

Author(s):

Alison J. Frontier ◽

Shukree Abdul-Rashed ◽

Connor Holt

Keyword(s):

Natural Products ◽

Small Molecules ◽

Natural Product ◽

Natural Product Synthesis ◽

Pericyclic Reactions ◽

Prins Reaction ◽

Prins Cyclization ◽

Synthetic Utility ◽

Cascade Processes ◽

Saturated Heterocycles

This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019.1 Introduction1.1 Alkyne-Carbonyl Coupling Pathways1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles)2.1 Early Work2.2 Halide as Terminal Nucleophile2.3 Oxygen as Terminal Nucleophile2.4 Arene as Terminal Nucleophile (Intermolecular)2.5 Arene Terminal Nucleophile (Intramolecular)2.6 Cyclizations Terminated by Elimination3 Synthetic Utility of Alkynyl Prins Annulation3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo- addition-Oxidation Sequence3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors3.3 Alkynyl Prins Cyclization in Natural Product Synthesis4 Alkynyl Aza-Prins Annulation4.1 Iminium Electrophiles4.2 Activated Iminium Electrophiles5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis6 Summary and Outlook

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