Computational drug design

Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes...

Revealing protein binding sites with other molecules, such as nucleic acids, peptides, or small ligands, sheds light on disease mechanism elucidation and novel drug design. With the explosive growth of proteins in sequence databases, how to accurately and efficiently identify these binding sites from sequences becomes essential. However, current methods mostly rely on expensive multiple sequence alignments or experimental protein structures, limiting their genome-scale applications. Besides, these methods haven't fully explored the geometry of the protein structures...

Biosimilar development refers to the process of creating a biologic drug that is similar to an existing approved biologic drug, also known as a reference drug. Due to the complex nature of biologics drugs and the inherent variability in their manufacturing process biosimilars are not identical but highly similar to the reference drug in terms of quality, safety, and efficacy. Efficacy and safety trials for biosimilars involve large numbers of patients to confirm comparable clinical performance of the biosimilar and the reference product in appropriately sensitive clinical indications and for appropriate sensitive endpoints...

Among the most prevalent forms of cancer are breast, lung, colon-rectum, and prostate cancers, and breast cancer is a major global health challenge, contributing to 2.26 million cases with approximately 685,000 deaths worldwide in 2020 alone, typically beginning in the milk ducts or lobules that produce and transport milk during lactation and it is becoming challenging to treat as the tissues are developing resistance, which makes urgent calls for new multitargeted drugs. The multitargeted drug design provides a better solution, simultaneously targeting multiple pathways, even when the drug resists one, it remains effective for others...

The natural product (-)-TAN-2483B is a fungal secondary metabolite which displays promising anti-cancer and immunomodulatory activity. Our previous syntheses of (-)-TAN-2483B and sidechain analogues uncovered inhibitory activity against Bruton's tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure-based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (-)-TAN-2483B and analogues in the Btk binding site...

BACKGROUND: Shenfu injection was derived from the classical Chinese medicine formula 'Shenfu decoction', which was widely used in the treatment of cardiovascular and cerebrovascular diseases in clinical practice. OBJECTIVES: Predict the main active ingredients, core targets, and related signaling pathways of Shenfu injection in the treatment of ischemic stroke. METHODS: Databases were used to collect the active ingredients and target information of Shenfu injection; GO and KEGG pathway enrichment analyses were performed using the David database...

BACKGROUND: The role of Forkhead Box D2 (FOXD2) in head and neck squamous cell carcinoma (HNSC) has never been studied. OBJECT: Our object was to explore the role of FOXD2 in HNSC. METHODS: Clinical data for patients with HNSC was obtained from TCGA. Our study examined the atypical expression of FOXD2 in both HNSC and pan-cancer, along with its diagnostic and prognostic implications, as well as the association between FOXD2 expression and clinical characteristics, immune infiltration, immune checkpoint genes, and MSI...

Drug repurposing, also referred to as drug repositioning or drug reprofiling, is a scientific approach to the detection of any new application for an already approved or investigational drug. It is a useful policy for the invention and development of new pharmacological or therapeutic applications of different drugs. The strategy has been known to offer numerous advantages over developing a completely novel drug for certain problems. Drug repurposing has numerous methodologies that can be categorized as target-oriented, drug-oriented, and problem-oriented...

Accurate calculation of drug-target affinity (DTA) is crucial for various applications in the pharmaceutical industry, including drug screening, design, and repurposing. However, traditional machine learning methods for calculating DTA often lack accuracy, posing a significant challenge in accurately predicting DTA. Fortunately, deep learning has emerged as a promising approach in computational biology, leading to the development of various deep learning-based methods for DTA prediction. To support researchers in developing novel and highly precision methods, we have provided a comprehensive review of recent advances in predicting DTA using deep learning...

In this paper we present a method that allows leveraging 3D electron density information to train a deep neural network pipeline to segment regions of high, medium and low electronegativity and classify substances as health hazardous or non-hazardous. We show that this can be used for use-cases such as cosmetics and food products. For this purpose, we first generate 3D electron density cubes using semiempirical molecular calculations for a custom European Chemicals Agency (ECHA) subset consisting of substances labelled as hazardous and non-hazardous for cosmetic usage...

Covid-19 disease caused by the deadly SARS-CoV-2 virus is a serious and threatening global health issue declared by the WHO as an epidemic. Researchers are studying the design and discovery of drugs to inhibit the SARS-CoV-2 virus due to its high mortality rate. The main Covid-19 virus protease (Mpro) and human transmembrane protease, serine 2 (TMPRSS2) are attractive targets for the study of antiviral drugs against SARS-2 coronavirus. Increasing consumption of herbal medicines in the community and a serious approach to these drugs have increased the demand for effective herbal substances...

More and more evidence shows that abnormal lipid metabolism leads to immune system dysfunction in AMD and promotes the occurrence of AMD by changing the homeostasis of ocular inflammation. However, the molecular mechanism underlying the effect of lipid metabolism on the phenotype and function of macrophages is still unclear, and the mechanism of association between AMD and cancer and COVID-19 has not been reported. The purpose of this study is to explore the interaction between lipid metabolism related genes, ferroptosis related genes and immunity in AMD, find out the key genes that affect the ferroptosis of AMD through lipid metabolism pathway and the molecular mechanism that mediates the action of macrophages, and find out the possible mechanism of lipid metabolism and potential co-therapeutic targets between AMD and cancer and COVID-19, so as to improve treatment decision-making and clinical results...

Triple-negative breast cancer (TNBC) lacks expressed protein targets, making therapy development challenging. Hydrogels offer a promising new route in this regard by improving the chemotherapeutic efficacy through increased solubility and sustained release. Moreover, subcutaneous hydrogel administration reduces patient burden by requiring less therapy and shorter treatment times. We recently established the design principles for the supramolecular assembly of single-domain coiled-coils into hydrogels. Using a modified computational design algorithm, we designed Q8, a hydrogel with rapid assembly for faster therapeutic hydrogel preparation...

Understanding protein structures is crucial for various bioinformatics research, including drug discovery, disease diagnosis, and evolutionary studies. Protein structure classification is a critical aspect of structural biology, where supervised machine learning algorithms classify structures based on data from databases such as Protein Data Bank (PDB). However, the challenge lies in designing numerical embeddings for protein structures without losing essential information. Although some effort has been made in the literature, researchers have not effectively and rigorously combined the structural and sequence-based features for efficient protein classification to the best of our knowledge...

Traditional Chinese medicine is precious treasure of ancient Chinese science and a key to unlocking the treasure trove of Chinese civilization. To elucidate the efficacy and mechanism of traditional Chinese medicines, scientists have been engaged in the research on the molecular basis and regulatory targets. Molecular docking is a computer-aided drug design method capable of visualizing the interaction between components and target proteins. With the progress in the modernization of traditional Chinese medicine and the advancement of algorithms and computing power, molecular docking has become an essential approach in the development of new traditional Chinese medicines...

Epilepsy is a complex disease spanning across multiple scales, from ion channels in neurons to neuronal circuits across the entire brain. Over the past decades, computational models have been used to describe the pathophysiological activity of the epileptic brain from different aspects. Traditionally, each computational model can aid in optimizing therapeutic interventions, therefore, providing a particular view to design strategies for treating epilepsy. As a result, most studies are concerned with generating specific models of the epileptic brain that can help us understand the certain machinery of the pathological state...

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (Mpro ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug...

AutoDock Vina (Vina) stands out among numerous molecular docking tools due to its precision and comparatively high speed, playing a key role in the drug discovery process. Hardware acceleration of Vina on FPGA platforms offers a high energy-efficiency approach to speed up the docking process. However, previous FPGA-based Vina accelerators exhibit several shortcomings: 1) Simple uniform quantization results in inevitable accuracy drop; 2) Due to Vina's complex computing process, the evaluation and optimization phase for hardware design becomes extended; 3) The iterative computations in Vina constrain the potential for further parallelization...

The important role that the neurotrophin tyrosine kinase receptor - TrkB has in the pathogenesis of several neurodegenerative conditions such are Alzheimer's disease, Parkinson's disease, Huntington's disease, has been well described. This shouldn't be a surprise, since in the physiological conditions, once activated by brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5), the TrkB receptor promotes neuronal survival, differentiation and synaptic function. Considering that the natural ligands for TrkB receptor are large proteins, it is a challenge to discover small molecule capable to mimic their effects...

BACKGROUND: Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide and is a hot topic in cardiovascular disease research. Western medicine treats CHD with stent implantation, anti-angina pectoris, anti-platelet aggregation and other operations or drugs. According to the whole concept and the characteristics of syndrome differentiation, traditional Chinese medicine (TCM) treats CHD according to different syndromes and points out that qi deficiency and blood stasis are the basic pathogenesis of CHD...