Abstract: Accurate prediction of protein-ligand binding affinity is crucial in structure-based drug design but remains some challenges even with recent advances in deep learning: (1) Existing methods neglect the edge information in protein and ligand structure data; (2) current attention mechanisms struggle to capture true binding interactions in the small dataset. Herein, we proposed SEGSA_DTA, a SuperEdge Graph convolution-based and Supervised Attention-based Drug-Target Affinity prediction method, where the super edge graph convolution can comprehensively utilize node and edge information and the multi-supervised attention module can efficiently learn the attention distribution consistent with real protein-ligand interactions. Results on the multiple datasets show that SEGSA_DTA outperforms current state-of-the-art methods. We also applied SEGSA_DTA in repurposing FDA-approved drugs to identify potential coronavirus disease 2019 (COVID-19) treatments. Besides, by using SHapley Additive exPlanations (SHAP), we found that SEGSA_DTA is interpretable and further provides a new quantitative analytical solution for structure-based lead optimization.

Abstract: We draw from the assumption that similarities between pathogens at both pathogen protein and host protein level, may provide the appropriate framework to identify and rank candidate drugs to be used against a specific pathogen. Vir2Drug is a drug repurposing tool that uses network-based approaches to identify and rank candidate drugs for a specific pathogen, combining information obtained from: (a) ranked pathogen-to-pathogen networks based on protein similarities between pathogens, (b) taxonomy distance between pathogens and (c) drugs targeting specific pathogen's and host proteins. The underlying pathogen networks are used to screen drugs by means of specific methodologies that account for either the host or pathogen's protein targets. Vir2Drug is a useful and yet informative tool for drug repurposing against known or unknown pathogens especially in periods where the emergence for repurposed drugs plays significant role in handling viral outbreaks, until reaching a vaccine. The web tool is available at: https://bioinformatics.cing.ac.cy/vir2drug, https://vir2drug.cing-big.hpcf.cyi.ac.cy.

Abstract: Finding an effective drug to prevent or treat COVID-19 is of utmost importance in tcurrent pandemic. Since developing a new treatment takes a significant amount of time, drug repurposing can be an effective option for achieving a rapid response. This study used a combined in silico virtual screening protocol for candidate SARS-CoV-2 PL(pro) inhibitors. The Drugbank database was searched first, using the Informational Spectrum Method for Small Molecules, followed by molecular docking. Gramicidin D was selected as a peptide drug, showing the best in silico interaction profile with PL(pro). After the expression and purification of PL(pro), gramicidin D was screened for protease inhibition in vitro and was found to be active against PL(pro). The current study's findings are significant because it is critical to identify COVID-19 therapies that are efficient, affordable, and have a favorable safety profile.

Abstract: Recent developments in deep learning, coupled with an increasing number of sequenced proteins, have led to a breakthrough in life science applications, in particular in protein property prediction. There is hope that deep learning can close the gap between the number of sequenced proteins and proteins with known properties based on lab experiments. Language models from the field of natural language processing have gained popularity for protein property predictions and have led to a new computational revolution in biology, where old prediction results are being improved regularly. Such models can learn useful multipurpose representations of proteins from large open repositories of protein sequences and can be used, for instance, to predict protein properties. The field of natural language processing is growing quickly because of developments in a class of models based on a particular model-the Transformer model. We review recent developments and the use of large-scale Transformer models in applications for predicting protein characteristics and how such models can be used to predict, for example, post-translational modifications. We review shortcomings of other deep learning models and explain how the Transformer models have quickly proven to be a very promising way to unravel information hidden in the sequences of amino acids.

Abstract: Quinazolines are nitrogen-containing heterocycles that consist of a benzene ring fused with a pyrimidine ring. Quinazolinones, oxidized quinazolines, are promising compounds with a wide range of biological activities. In the pharmaceutical field, quinazolinones are the building blocks of more than 150 naturally occurring alkaloids isolated from different plants, microorganisms, and animals. Scientists give a continuous interest in this moiety due to their stability and relatively easy methods for preparation. Their lipophilicity is another reason for this interest as it helps quinazolinones in penetration through the blood-brain barrier which makes them suitable for targeting different central nervous system diseases. Various modifications to the substitutions around the quinazolinone system changed their biological activity significantly due to changes in their physicochemical properties. Structure-activity relationship (SAR) studies of quinazolinone revealed that positions 2, 6, and 8 of the ring systems are significant for different pharmacological activities. In addition, it has been suggested that the addition of different heterocyclic moieties at position 3 could increase activity. In this review, we will highlight the chemical properties of quinazolinones, including their chemical reactions and different methods for their preparation. Moreover, we will try to modify some of the old SAR studies according to their updated biological activities in the last twelve years.

Abstract: Drug distribution is an important process in pharmacokinetics because it has the potential to influence both the amount of medicine reaching the active sites and the effectiveness as well as safety of the drug. The main causes of 90% of drug failures in clinical development are lack of efficacy and uncontrolled toxicity. In recent years, several advances and promising developments in drug distribution property prediction have been achieved, especially in silico, which helped to drastically reduce the time and expense of screening undesired drug candidates. In this study, we provide comprehensive knowledge of drug distribution background, influencing factors, and artificial intelligence-based distribution property prediction models from 2019 to the present. Additionally, we gathered and analyzed public databases and datasets commonly utilized by the scientific community for distribution prediction. The distribution property prediction performance of five large ADMET prediction tools is mentioned as a benchmark for future research. On this basis, we also offer future challenges in drug distribution prediction and research directions. We hope that this review will provide researchers with helpful insight into distribution prediction, thus facilitating the development of innovative approaches for drug discovery.

Abstract: Leishmania tropica is a tropical parasite causing cutaneous leishmaniasis (CL) in humans. Leishmaniasis is a serious public health threat, affecting an estimated 350 million people in 98 countries. The global rise in antileishmanial drug resistance has triggered the need to explore novel therapeutic strategies against this parasite. In the present study, we utilized the recently available multidrug resistant L. tropica strain proteome data repository to identify alternative therapeutic drug targets based on comparative subtractive proteomic and druggability analyses. Additionally, small drug-like compounds were scanned against novel targets based on virtual screening and ADME profiling. The analysis unveiled 496 essential cellular proteins of L. tropica that were nonhomologous to the human proteome set. The druggability analyses prioritized nine parasite-specific druggable proteins essential for the parasite's basic cellular survival, growth, and virulence. These prioritized proteins were identified to have appropriate binding pockets to anchor small drug-like compounds. Among these, UDPase and PCNA were prioritized as the top-ranked druggable proteins. The pharmacophore-based virtual screening and ADME profiling predicted MolPort-000-730-162 and MolPort-020-232-354 as the top hit drug-like compounds from the Pharmit resource to inhibit L. tropica UDPase and PCNA, respectively. The alternative drug targets and drug-like molecules predicted in the current study lay the groundwork for developing novel antileishmanial therapies.

Abstract: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer due to its molecular heterogeneity and poor clinical outcomes. Analysis of circulating cell-free tumor nucleic acids (ctNAs) can improve our understanding of TNBC and provide efficient and non-invasive clinical biomarkers that may be representative of tumor heterogeneity. In this review, we summarize the potential of ctNAs to aid TNBC diagnosis and prognosis. For example, tumor fraction of circulating cell-free DNA (TFx) may be useful for molecular prognosis of TNBC: high TFx levels after neoadjuvant chemotherapy have been associated with shorter progression-free survival and relapse-free survival. Mutations and copy number variations of TP53 and PIK3CA/AKT genes in plasma may be important markers of TNBC onset, progression, metastasis, and for clinical follow-up. In contrast, the expression profile of circulating cell-free tumor non-coding RNAs (ctncRNAs) can be predictive of molecular subtypes of breast cancer and thus aid in the identification of TBNC. Finally, dysregulation of some circulating cell-free tumor miRNAs (miR17, miR19a, miR19b, miR25, miR93, miR105, miR199a) may have a predictive value for chemotherapy resistance. In conclusion, a growing number of efforts are highlighting the potential of ctNAs for future clinical applications in the diagnosis, prognosis, and follow-up of TNBC.

Abstract: Compound identification in ligand-based virtual screening is limited by two key issues: the quality and the time needed to obtain predictions. In this sense, we designed OptiPharm, an algorithm that obtained excellent results in improving the sequential methods in the literature. In this work, we go a step further and propose its parallelization. Specifically, we propose a two-layer parallelization. Firstly, an automation of the molecule distribution process between the available nodes in a cluster, and secondly, a parallelization of the internal methods (initialization, reproduction, selection and optimization). This new software, called pOptiPharm, aims to improve the quality of predictions and reduce experimentation time. As the results show, the performance of the proposed methods is good. It can find better solutions than the sequential OptiPharm, all while reducing its computation time almost proportionally to the number of processing units considered.

Abstract: Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn's disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided (in silico) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.