使用精简化掩饰式变压器基础的预训练功能在体中识别 histone deacetylase 抑制剂
Tuan Vinh1, Thanh-Hoang Nguyen-Vo2, Viet-Tuan Le2
1Department of Chemistry, Emory University, 201 Dowman Drive, Atlanta, GA 30322-1007, United States.
Methods (San Diego, Calif.)
|November 24, 2024
概括
一个新的精简化掩饰式基于变压器的预训练 (SMTP) 编码器有效地识别了基因素脱乙酶 (HDAC) 抑制剂. 这种计算方法对开发与HDACs相关的各种疾病的治疗方法充满希望.
科学领域:
- 生物化学 生物化学
- 计算化学计算化学
- 药物发现 药物发现 药物发现
背景情况:
- 基因脱乙酶 (HDACs) 调节基因表达,并与许多疾病有关.
- 识别强大的HDAC抑制剂对于治疗开发至关重要.
- 现有的HDAC抑制剂识别的in silico方法存在局限性.
研究的目的:
- 开发一种用于识别HDAC抑制剂的新型计算方法.
- 介绍一个基于变压器的精简化掩饰预训练 (SMTP) 编码器用于分子特征生成.
- 创建和评估用于HDAC异型分类的机器学习模型.
主要方法:
- 开发了一种基于转换器预训练 (SMTP) 的精简化面具编码器,使用面具基于注意力的学习.
- 在190万个分子上训练了SMTP编码器.
- 使用SMTP生成的特性用于11个不同的HDAC异型分类任务.
- 开发并比较使用SMTP特征的机器学习模型与其他特征集.
主要成果:
- 尽管SMTP编码器具有轻量级的性质和较小的培训数据集,但它仍表现出具有竞争力的区分能力.
- 用SMTP功能训练的机器学习模型在11个分类任务中的8个中表现优于使用其他功能集的机器学习模型.
- 化学多样性分析验证了编码器在分子类差异化方面的能力.
结论:
- SMTP编码器提供了一种强大而高效的工具,用于生成用于识别HDAC抑制剂的分子特征.
- 这种方法提高了机器学习模型在分类HDAC异型时的准确性.
- 开发的方法有可能推动针对HDAC的药物发现工作.
相关概念视频
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:25Spreading of Chromatin Modifications
The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer is an enzyme that can...
Writers
The writer is an enzyme that can...
02:36Chromatin Immunoprecipitation- ChIP
Chromatin immunoprecipitation, or ChIP, is an antibody-based technique used to identify sites on DNA that bind to transcription factors of interest or histone proteins. It also helps determine the type of histone modifications such as acetylation, phosphorylation, or methylation.
Types of ChIP
ChIP can be divided into two types - X-ChIP and N-ChIP. X-ChIP involves in vivo cross-linking of histones and regulatory proteins to DNA, fragmenting the DNA by sonication, and isolating the protein-DNA...
Types of ChIP
ChIP can be divided into two types - X-ChIP and N-ChIP. X-ChIP involves in vivo cross-linking of histones and regulatory proteins to DNA, fragmenting the DNA by sonication, and isolating the protein-DNA...
02:38Heterochromatin
The extent of chromatin compaction can be studied by staining chromatin using specific DNA binding dyes. Under the microscope, the dense-compacted regions that take up more dye are called heterochromatin. Heterochromatin is further classified into two forms – constitutive heterochromatin and facultative heterochromatin.
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
Constitutive heterochromatin: It is a highly compact region of chromatin that is mostly concentrated in the centromere and telomere. Unlike euchromatin, the amino acid at 9th...
01:32Chromatin Modification in iPS Cells
Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
01:12The Nucleosome Core Particle
Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...