Abstract:Inhibiting the tubulin-microtubules (Tub-Mts) system is a classic and rational approach for treating different types of cancers. A large amount of data on inhibitors in the clinic supports Tub-Mts as a validated target. However, most of the inhibitors reported thus far have been developed around common chemical scaffolds covering a narrow region of the chemical space with limited innovation. This manuscript aims to discuss the first activity landscape and scaffold content analysis of an assembled and curated c… Show more
“…Recently, constellation plots have been used to describe a library of antidiabetic natural products [25] and a collection of tubulin inhibitors. [26]…”
Section: Constellation Plotsmentioning
confidence: 99%
“…Of note, only a fraction of the total data is presented in the constellation plot: the compounds forming analog series; in this case, we included only analog series consisting of at least three compounds. Recently, constellation plots have been used to describe a library of antidiabetic natural products [25] and a collection of tubulin inhibitors [26] …”
Section: Chemical Space: Visual Representationmentioning
The importance of epigenetic drug and probe discovery is on the rise. This is not only paramount to identify and develop therapeutic treatments associated with epigenetic processes but also to understand the underlying epigenetic mechanisms involved in biological processes. To this end, chemical vendors have been developing synthetic compound libraries focused on epigenetic targets to increase the probabilities of identifying promising starting points for drug or probe candidates. However, the chemical contents of these data sets, the distribution of their physicochemical properties, and diversity remain unknown. To fill this gap and make this information available to the scientific community, we report a comprehensive analysis of eleven libraries focused on epigenetic targets containing more than 50,000 compounds. We used well-validated chemoinformatics approaches to characterize these sets, including novel methods such as automated detection of analog series and visual representations of the chemical space based on Constellation Plots and Extended Chemical Space Networks. This work will guide the efforts of experimental groups working on high-throughput and medium-throughput screening of epigenetic-focused libraries. The outcome of this work can also be used as a reference to design and describe novel focused epigenetic libraries.
“…Recently, constellation plots have been used to describe a library of antidiabetic natural products [25] and a collection of tubulin inhibitors. [26]…”
Section: Constellation Plotsmentioning
confidence: 99%
“…Of note, only a fraction of the total data is presented in the constellation plot: the compounds forming analog series; in this case, we included only analog series consisting of at least three compounds. Recently, constellation plots have been used to describe a library of antidiabetic natural products [25] and a collection of tubulin inhibitors [26] …”
Section: Chemical Space: Visual Representationmentioning
The importance of epigenetic drug and probe discovery is on the rise. This is not only paramount to identify and develop therapeutic treatments associated with epigenetic processes but also to understand the underlying epigenetic mechanisms involved in biological processes. To this end, chemical vendors have been developing synthetic compound libraries focused on epigenetic targets to increase the probabilities of identifying promising starting points for drug or probe candidates. However, the chemical contents of these data sets, the distribution of their physicochemical properties, and diversity remain unknown. To fill this gap and make this information available to the scientific community, we report a comprehensive analysis of eleven libraries focused on epigenetic targets containing more than 50,000 compounds. We used well-validated chemoinformatics approaches to characterize these sets, including novel methods such as automated detection of analog series and visual representations of the chemical space based on Constellation Plots and Extended Chemical Space Networks. This work will guide the efforts of experimental groups working on high-throughput and medium-throughput screening of epigenetic-focused libraries. The outcome of this work can also be used as a reference to design and describe novel focused epigenetic libraries.
“…In contrast, analog series with more different structures are far apart. Recently, López-López E. et al proposed a methodology to navigate interactively/dynamically in the chemical space using constellation plots [ 96 ] by implementing the DataWarrior software [ 76 ]. All this allows applying filters for compounds, analogous series, biological activity, and other properties of pharmaceutical interest using an intuitive platform that is well suited for all users (expert or non-experts on chemoinformatics tools).…”
Section: Exploring For Structure–activity Relationships (Stars) In Chemical Spacementioning
confidence: 99%
“…In contrast, cyan-to-blue colored dots indicate analog series with mostly inactive molecules. Full details of the study are described elsewhere [ 96 ]. Fig.…”
Section: Exploring For Structure–activity Relationships (Stars) In Chemical Spacementioning
confidence: 99%
“…Linking lines represent shared molecules between two analog series. Figure was adapted from López-López E. et al [ 96 ] …”
Section: Exploring For Structure–activity Relationships (Stars) In Chemical Spacementioning
The concept of chemical space is a cornerstone in chemoinformatics, and it has broad conceptual and practical applicability in many areas of chemistry, including drug design and discovery. One of the most considerable impacts is in the study of structure–property relationships where the property can be a biological activity or any other characteristic of interest to a particular chemistry discipline. The chemical space is highly dependent on the molecular representation that is also a cornerstone concept in computational chemistry. Herein, we discuss the recent progress on chemoinformatic tools developed to expand and characterize the chemical space of compound data sets using different types of molecular representations, generate visual representations of such spaces, and explore structure–property relationships in the context of chemical spaces. We emphasize the development of methods and freely available tools focusing on drug discovery applications. We also comment on the general advantages and shortcomings of using freely available and easy-to-use tools and discuss the value of using such open resources for research, education, and scientific dissemination.
Modification of the tubulin‐microtubule (Tub‐Mts) system has generated effective strategies for developing different treatments for cancer. A huge amount of clinical data about inhibitors of the tubulin‐microtubule system have supported and validated the studies on this pharmacological target. However, many tubulin‐microtubule inhibitors have been developed from representative and common scaffolds that cover a small region of the chemical space with limited structural innovation. The main goal of this study is to develop the first consensus virtual screening protocol for natural products (ligand‐ and structure‐based drug design methods) tuned for the identification of new potential inhibitors of the Tub‐Mts system. A combined strategy that involves molecular similarity, molecular docking, pharmacophore modeling, and in silico ADMET prediction has been employed to prioritize the selections of potential inhibitors of the Tub‐Mts system. Five compounds were selected and further studied using molecular dynamics and binding energy predictions to characterize their possible binding mechanisms. Their structures correspond to 5‐[2‐(4‐hydroxy‐3‐methoxyphenyl) ethyl]‐2,3‐dimethoxyphenol (1), 9,10‐dihydro‐3,4‐dimethoxy‐2,7‐phenanthrenediol (2), 2‐(3,4‐dimethoxyphenyl)‐5,7‐dihydroxy‐6‐methoxy‐4H‐1‐benzopyran‐4‐one (3), 13,14‐epoxyparvifoline‐4’,5’,6’‐trimethoxybenzoate (4), and phenylmethyl 6‐hydroxy‐2,3‐dimethoxybenzoate (5). Compounds 1–3 have been associated with literature reports that confirm their activity against several cancer cell lines, thus supporting the utility of this protocol.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
