Recent updates in click and computational chemistry for drug discovery and development

Cai, Jiang Hong; Zhu, Xuan Zhe; Guo, Peng Yue; Rose, Peter G.; Liu, Xiao Tong; Liu, Xia; Zhu, Yi‐Zhun

doi:10.3389/fchem.2023.1114970

Cited by 6 publications

(5 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, aromatic 2-chlorobenzaldehyde (3d) was used and the desired compound 5ad was obtained in 36% yield (Scheme 2 and Figure 2). Like the oxindole scaffold, 1,2,3-triazole is also considered a privileged unit in drug discovery since compounds having this structure have a broad spectrum of biological activities, and have been widely used to create anticancer drug candidates [24,25]. The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, or commonly entitled "click" reaction, is a widely and straightforward tool to access the 1,2,3-triazole ring [26,27].…”

Section: Synthesismentioning

confidence: 99%

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

Marques,

González-Bakker,

Padrón

2024

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here, we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell lines, among them, non-small cell lung carcinoma, cervical adenocarcinoma, breast cancer and colon adenocarcinoma. The most potent compounds 8d, 8h and 8k showed GI50 values in the range of 1–10 μM.

show abstract

Section: Synthesismentioning

confidence: 99%

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

Marques,

González-Bakker,

Padrón

2024

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

show abstract

“…Such strategies include the activation of cryptic or occult biosynthetic gene clusters that remain otherwise silent ( Macheleidt et al, 2016 ), which can be achieved through the manipulation of culture conditions ( Pan et al, 2019 ), micro-organism co-cultures ( Bertrand et al, 2014 ) or exposure to small molecule epigenetic modulators ( Pillay et al, 2022 ), among other approaches. The expansion of chemical space through various strategies entails the parallel development of new chemical methods capable of solving previously untested synthetic paths, so as to produce compounds corresponding to the newly designed structures and in cost-effective yields ( Cai et al, 2023 ).…”

Section: Natural Products As Sources Of Chemical Diversitymentioning

confidence: 99%

On the importance for drug discovery of a transnational Latin American database of natural compound structures

Thomson

2023

Front. Pharmacol.

View full text Add to dashboard Cite

“…The advent of computational chemistry and advancements in synthetic methodologies have brought about a paradigm shift in compound discovery and optimization [5][6][7]. In recent years, in silico reaction-based enumeration has gained prominence, offering a novel solution to overcome the limitations inherent in traditional HTS methods [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

AI-driven drug discovery: identification and optimization of ALDH3A1 selective inhibitors with nanomolar activity

Jain,

Yasgar,

Dalal

et al. 2024

Preprint

View full text Add to dashboard Cite

In the field of medicinal chemistry, the discovery of novel compounds with therapeutic potential is of utmost importance. However, the conventional approach to drug discovery, relying on high-throughput screening (HTS), encounters limitations such as reagent availability and labor costs. Although a hit-finding campaign starts with a virtual screen of millions of compounds, the hit-to-lead and lead optimization stages often require designing, synthesizing, and profiling thousands of analogs before selecting clinical candidates. Recent advances offer an innovative solution - the virtual generation of billions of synthetically feasible compounds with an impressive 80% success rate for synthesis. This breakthrough has the potential to significantly expand the chemical space available for purchase and experimental validation, bringing about a revolution in the field. Our study presents a comprehensive approach to compound discovery and optimization, harnessing quantitative high-throughput screening (qHTS), chemical databases, and reaction-based enumeration. To further enhance the synthesis process and gain deeper insights into compound formation, we utilize the Reaction Cookbook from Biosolveit, which comprises reaction SMARTs for around 300 chemical reactions. By employing this wide range of reactions, we aim to uncover the full spectrum of a chemotype's potential and customize its structure to optimize desired properties. As an illustration of this approach, our work on the ALDH3A1 project resulted in the synthesis of 50 compounds, with 21 of them exhibiting activity (negative curve class values; hit-rate ~42%). Among these active compounds, 6 displayed IC50 values lower than 30 µM and efficacy values less than -50%, with the most potent compound achieving an impressive potency of 447 nM. This study demonstrates the successful synergy between in-silico reaction-based analogs enumeration, molecular modeling and AI/ML-based techniques in identifying compounds with improved biological activity, offering promising prospects for the development of ALDH3A1-targeting agents as potential cancer therapeutics. Computational workflows developed in this study can be used for similar target-based drug discovery campaigns.

show abstract

Recent updates in click and computational chemistry for drug discovery and development

Cited by 6 publications

References 52 publications

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

On the importance for drug discovery of a transnational Latin American database of natural compound structures

AI-driven drug discovery: identification and optimization of ALDH3A1 selective inhibitors with nanomolar activity

Contact Info

Product

Resources

About