Current Medicinal Chemistry - Volume 29, Issue 5, 2022

Protein-ligand interactions are necessary for majority protein functions. Adenosine- 5’-triphosphate (ATP) is one such ligand that plays vital role as a coenzyme in providing energy for cellular activities, catalyzing biological reaction and signaling. Knowing ATP binding residues of proteins is helpful for annotation of protein function and drug design. However, due to the huge amounts of protein sequences influx into databases in the post-genome era, experimentally identifying ATP binding residues is costineffective and time-consuming. To address this problem, computational methods have been developed to predict ATP binding residues. In this review, we briefly summarized the application of machine learning methods in detecting ATP binding residues of proteins. We expect this review will be helpful for further research.

Malaria caused by Plasmodium falciparum is one of the major infectious diseases in the world. It is essential to exploit an effective method to predict secretory proteins of malaria parasites to develop effective cures and treatment. Biochemical assays can provide details for accurate identification of the secretory proteins, but these methods are expensive and time-consuming. In this paper, we summarized the machine learningbased identification algorithms and compared the construction strategies between different computational methods. Also, we discussed the use of machine learning to improve the ability of algorithms to identify proteins secreted by malaria parasites.

DNA methylation is an important mode of regulation in epigenetic mechanisms, and it is one of the research foci in the field of epigenetics. DNA methylation modification affects a series of biological processes, such as eukaryotic cell growth, differentiation, and transformation mechanisms, by regulating gene expression. In this review, we systematically summarized the DNA methylation databases, prediction tools for DNA methylation modification, machine learning algorithms for predicting DNA methylation modification, and the relationship between DNA methylation modification and diseases such as hypertension, Alzheimer's disease, diabetic nephropathy, and cancer. An in-depth understanding of DNA methylation mechanisms can promote accurate prediction of DNA methylation modifications and the treatment and diagnosis of related diseases.

Chemotherapy is often the primary and most effective anticancer treatment; however, drug resistance remains a major obstacle to it being curative. Recent studies have demonstrated that non-coding RNAs (ncRNAs), especially microRNAs and long non-coding RNAs, are involved in drug resistance of tumor cells in many ways, such as modulation of apoptosis, drug efflux and metabolism, epithelial-to-mesenchymal transition, DNA repair, and cell cycle progression. Exploring the relationships between ncRNAs and drug resistance will not only contribute to our understanding of the mechanisms of drug resistance and provide ncRNA biomarkers of chemoresistance, but will also help realize personalized anticancer treatment regimens. Due to the high cost and low efficiency of biological experimentation, many researchers have opted to use computational methods to identify ncRNA biomarkers associated with drug resistance. In this review, we summarize recent discoveries related to ncRNA-mediated drug resistance and highlight the computational methods and resources available for ncRNA biomarkers involved in chemoresistance.

Cancer is one of the leading causes of death worldwide and the underlying angiogenesis represents one of the hallmarks of cancer. Efforts are already under way for the discovery of anti-angiogenic peptides (AAPs) as a promising therapeutic route, which tackle the formation of new blood vessels. As such, the identification of AAPs constitutes a viable path for understanding their mechanistic properties pertinent for the discovery of new anti-cancer drugs. In spite of the abundance of peptide sequences in public databases, experimental efforts in the identification of anti-angiogenic peptides have progressed very slowly owing to high expenditures and laborious nature. Owing to its inherent ability to make sense of large volumes of data, machine learning (ML) represents a lucrative technique that can be harnessed for peptide-based drug discovery. In this review, we conducted a comprehensive and comparative analysis of ML-based AAP predictors in terms of their employed feature descriptors, ML algorithms, cross-validation methods and prediction performance. Moreover, the common framework of these AAP predictors and their inherent weaknesses are also discussed. Particularly, we explore future perspectives for improving the prediction accuracy and model interpretability, which represent an interesting avenue for overcoming some of the inherent weaknesses of existing AAP predictors. We anticipate that this review would assist researchers in the rapid screening and identification of promising AAPs for clinical use.

MicroRNAs (miRNAs) are central players that regulate the post-transcriptional processes of gene expression. Binding of miRNAs to target mRNAs can repress their translation by inducing the degradation or by inhibiting the translation of the target mRNAs. Highthroughput experimental approaches for miRNA target identification are costly and timeconsuming, depending on various factors. It is vitally important to develop bioinformatics methods for accurately predicting miRNA targets. With the increase of RNA sequences in the post-genomic era, bioinformatics methods are being developed for miRNA studies especially for miRNA target prediction. This review summarizes the current development of state-of-the-art bioinformatics tools for miRNA target prediction, points out the progress and limitations of the available miRNA databases, and their working principles. Finally, we discuss the caveat and perspectives of the next-generation algorithms for the prediction of miRNA targets.

Owing to its superior performance, the Transformer model, based on the 'Encoder- Decoder' paradigm, has become the mainstream model in natural language processing. However, bioinformatics has embraced machine learning and has led to remarkable progress in drug design and protein property prediction. Cell-penetrating peptides (CPPs) are a type of permeable protein that is a convenient 'postman' in drug penetration tasks. However, only a few CPPs have been discovered, limiting their practical applications in drug permeability. CPPs have led to a new approach that enables the uptake of only macromolecules into cells (i.e., without other potentially harmful materials found in the drug). Most previous studies have utilized trivial machine learning techniques and hand-crafted features to construct a simple classifier. CPPFormer was constructed by implementing the attention structure of the Transformer, rebuilding the network based on the characteristics of CPPs according to their short length, and using an automatic feature extractor with a few manually engineered features to co-direct the predicted results. Compared to all previous methods and other classic text classification models, the empirical results show that our proposed deep model-based method achieves the best performance, with an accuracy of 92.16% in the CPP924 dataset, and passes various index tests.

Sumoylation of proteins is an important reversible post-translational modification of proteins and mediates a variety of cellular processes. Sumo-modified proteins can change their subcellular localization, activity, and stability. In addition, it also plays an important role in various cellular processes such as transcriptional regulation and signal transduction. The abnormal sumoylation is involved in many diseases, including neurodegeneration and immune-related diseases, as well as the development of cancer. Therefore, identification of the sumoylation site (SUMO site) is fundamental to understanding their molecular mechanisms and regulatory roles. In contrast to labor-intensive and costly experimental approaches, computational prediction of sumoylation sites in silico has also attracted much attention for its accuracy, convenience, and speed. At present, many computational prediction models have been used to identify SUMO sites, but their contents have not been comprehensively summarized and reviewed. Therefore, the research progress of relevant models is summarized and discussed in this paper. We have briefly summarized the development of bioinformatics methods for sumoylation site prediction by mainly focusing on the benchmark dataset construction, feature extraction, machine learning method, published results, and online tools. We hope that this review will provide more help for wet-experimental scholars.

Resistance to antibiotics has existed in the health care and community settings. Thus, developing novel antibiotics is urgent. Methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK) is crucial for the survival of bacteria, making it a novel antimicrobial target. In the past decade, the most commonly reported PK inhibitors include indole, flavonoid, phenazine derivatives from natural products’ small molecules or their analogs, or virtual screening from small molecule compound library. This review covers the PK inhibitors and their antimicrobial activities reported from the beginning of 2011 through mid-2020. The Structure-Activity Relationships (SARs) were discussed briefly as well.

Background: Malignant tumor is a disease that seriously threatens human health. At present, more and more research results show that the pathogenesis of different tumors is very complicated, and the methods of clinical treatment are also diverse. This review analyzes and summarizes the role of fat mass and obesity associated (FTO) gene in different tumors, and provides a reference value for research and drug treatment methods. Methods: We conducted a comprehensive literature search using the database. According to the main purpose of the article, irrelevant articles were excluded from the research summary and included in the relevant articles. Finally, the relevant information of the article was summarized. Result: In this article, the relationship between malignant tumors and FTO is introduced by citing many documents. In addition, the inhibitors that act on FTO are listed. Conclusion: This article has shown thatFTO protein is a demethylase that can regulate N6-methyladenosine (m⁶A) levels in mRNA and plays a key role in the progression and resistance of various tumors such as leukemia, breast cancer, and lung cancer.

Depression is a common mental illness that belongs to the category of emotional disorders that causes serious damage to the health and life of patients, while inflammation is considered to be one of the important factors that cause depression. In this case, it might be important to explore the possible therapeutic approach by using natural compounds exerting an anti-inflammatory and antidepressant effect, which has not been systematically reviewed recently. Hence, this review aims to systematically sort the literature related to the mechanism of exerting an antidepressant effect through antiinflammatory actions and to summarize the related natural products in the past 20 years in terms of several inflammatory-related pathways (i.e., the protein kinase B (Akt) pathway, monoamine neurotransmitters (5-hydroxytryptamine and norepinephrine) (5-HT and NE), the nod-like receptor protein-3 (NLRP3) inflammasome, proinflammatory cytokines, neurotrophins, or cytokine-signaling pathways), which might provide a useful reference for the potential treatment of depression.