Dataset Information

Chemical Space Exploration of DprE1 Inhibitors Using Chemoinformatics and Artificial Intelligence.

ABSTRACT: Tuberculosis (TB), entrained by Mycobacterium tuberculosis, continues to be an enfeebling disease, killing nearly 1.5 million people in 2019, with 2 billion people worldwide affected by latent TB. The multidrug-resistant and totally drug-resistant emerging strains further exacerbate the TB infection. The cell wall of bacteria provides critical virulence components such as cell surface proteins, regulators, signal transduction proteins, and toxins. The cell wall biosynthesis pathway of Mycobacterium tuberculosis is exhaustively studied to discover novel drug targets. Decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1) is an important enzyme involved in the arabinogalactan biosynthetic pathway of Mycobacterium tuberculosis cell wall and is essential for both latent and persistent bacterial infection. We analyzed all known ∼1300 DprE1 inhibitors to gain deep insights into the chemogenomic space of DprE1-ligand complexes. Physicochemical descriptors of the DprE1 inhibitors showed a marked lipophilic character forming a cluster distinct from the existing TB drugs, as revealed by the principal component analysis. Similarity analysis using Murcko scaffolds and rubber band scaling revealed scarce representation of the chemical space. Further, Murcko scaffold analysis uncovered favorable and unfavorable scaffolds, where benzo and pyridine-based core scaffolds exhibit the highest biological activity, as evidenced by their MIC and IC₅₀ values. Automatic SAR and R-group decomposition analysis resulted in the identification of substructures responsible for the inhibitory activity of the DprE1 enzyme. Further, with activity cliff analysis, we observed prominent discontinuity in the SAR of DprE1 inhibitors, where even simple structural modification in the chemical scaffold resulted in significant potency difference, presumably due to the binding orientation and interaction in the active site. Thiophene, 6-membered aromatic rings, and unsubstituted benzene ring-based toxicophores were identified in the DprE1 chemical space using an artificial intelligence approach based on inductive logic programming. This paper, hence, ushers in new insights for the design and development of potent covalent and non-covalent DprE1 inhibitors and guides hit and lead optimization for the development of non-hazardous small molecule therapeutics for Mycobacterium tuberculosis.

SUBMITTER: Chhabra S

PROVIDER: S-EPMC8190903 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:In order to carry out a comprehensive design description of the specific architectural model of AI, the auxiliary model of AI and architectural spatial intelligence is deeply integrated, and flexible design is carried out according to the actual situation. AI assists in the generation of architectural intention and architectural form, mainly supporting academic and working theoretical models, promoting technological innovation, and thus improving the design efficiency of the architectural design industry. AI-aided architectural design enables every designer to achieve design freedom. At the same time, with the help of AI, architectural design can complete the corresponding work faster and more efficiently. With the help of AI technology, through the adjustment and optimization of keywords, AI automatically generates a batch of architectural space design schemes. Against this background, the auxiliary model of architectural space design is established through the literature research of the AI model, the architectural space intelligent auxiliary model, and the semantic network and the internal structure analysis of architectural space. Secondly, to ensure compliance with the three-dimensional characteristics of the architectural space from the data source, based on the analysis of the overall function and structure of space design, the intelligent design of the architectural space auxiliary by Deep Learning is carried out. Finally, it takes the 3D model selected in the UrbanScene3D data set as the research object, and the auxiliary performance of AI's architectural space intelligent model is tested. The research results show that with the increasing number of network nodes, the model fitting degree on the test data set and training data set is decreasing. The fitting curve of the comprehensive model shows that the intelligent design scheme of architectural space based on AI is superior to the traditional architectural design scheme. As the number of nodes in the network connection layer increases, the intelligent score of space temperature and humidity will continue to rise. The model can achieve the optimal intelligent auxiliary effect of architectural space. The research has practical application value for promoting the intelligent and digital transformation of architectural space design.

Project description:The monoamine oxidase (MAO) enzyme class is a prevalent target for many neurodegenerative and depressive disorders. Even though scrutinization of many promising drugs for the treatment of MAO inhibition has been carried out in recent times, a conclusive structural requirement for potent activity needs to be developed. Numerous approaches have been examined for the identification of structural features for potent MAO inhibitors (MAOIs) that mainly involve an array of computational studies, synthetic approaches, and biological evaluation. In this paper, we have analyzed ∼2200 well-known MAOIs to expand perceptions in the chemical space of MAOIs. The physicochemical properties of the MAOIs disclosed a discernible hydrophobic feature making a bunch discrete from the central nervous system (CNS) acting drugs, as exposed using the principal component analysis (PCA). The Murcko scaffold structure study revealed unfavorable and favorable scaffold structures, in both data sets, with the highest biological activity shown by the 3-phenyl-2H-chromen-2-one scaffold. This scaffold showed a polypharmacological effect. R-group disintegration and automatic structure-activity relationship (SAR) study resulted in identification of substructures responsible for the inhibitory bioactivity of the MAO-A and MAO-B enzymes. Moreover, with activity cliff analysis, significant biological activity was detected by simple molecular conversion in the chemical compound structure. In addition, we used the machine learning tool to generate a hypothesis wherein pyrazole, benzene ring, and amide containing structural functionalities can exhibit potential biological activities. This hypothesis revealed that CNS target drugs, C4155, C13390, C21265, C43862, C31524, C24810, C37100, C42075, and C43644, could be repurposed as valuable candidates for the MAO-B enzyme. For researchers, this study will bring new perceptions in the discovery and development of MAOIs and direct lead and hit optimization for the progress of small molecules beneficial for MAO-targeting associated diseases.

Dataset Information

Chemical Space Exploration of DprE1 Inhibitors Using Chemoinformatics and Artificial Intelligence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets