1,997 research outputs found
Molecular docking: Shifting paradigms in drug discovery
Molecular docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compounds of therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing a priori the chemical structure of other target modulators. Although it was originally developed to help understanding the mechanisms of molecular recognition between small and large molecules, uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how molecular docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacology, drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence
Computational Approaches to Drug Profiling and Drug-Protein Interactions
Despite substantial increases in R&D spending within the pharmaceutical industry, denovo drug design has become a time-consuming endeavour. High attrition rates led to a
long period of stagnation in drug approvals. Due to the extreme costs associated with
introducing a drug to the market, locating and understanding the reasons for clinical failure
is key to future productivity. As part of this PhD, three main contributions were made in
this respect. First, the web platform, LigNFam enables users to interactively explore
similarity relationships between ‘drug like’ molecules and the proteins they bind. Secondly,
two deep-learning-based binding site comparison tools were developed, competing with
the state-of-the-art over benchmark datasets. The models have the ability to predict offtarget interactions and potential candidates for target-based drug repurposing. Finally, the
open-source ScaffoldGraph software was presented for the analysis of hierarchical scaffold
relationships and has already been used in multiple projects, including integration into a
virtual screening pipeline to increase the tractability of ultra-large screening experiments.
Together, and with existing tools, the contributions made will aid in the understanding of
drug-protein relationships, particularly in the fields of off-target prediction and drug
repurposing, helping to design better drugs faster
Artificial intelligence, machine learning, and drug repurposing in cancer
Introduction: Drug repurposing provides a cost-effective strategy to re-use approved drugs for new medical indications. Several machine learning (ML) and artificial intelligence (AI) approaches have been developed for systematic identification of drug repurposing leads based on big data resources, hence further accelerating and de-risking the drug development process by computational means. Areas covered: The authors focus on supervised ML and AI methods that make use of publicly available databases and information resources. While most of the example applications are in the field of anticancer drug therapies, the methods and resources reviewed are widely applicable also to other indications including COVID-19 treatment. A particular emphasis is placed on the use of comprehensive target activity profiles that enable a systematic repurposing process by extending the target profile of drugs to include potent off-targets with therapeutic potential for a new indication. Expert opinion: The scarcity of clinical patient data and the current focus on genetic aberrations as primary drug targets may limit the performance of anticancer drug repurposing approaches that rely solely on genomics-based information. Functional testing of cancer patient cells exposed to a large number of targeted therapies and their combinations provides an additional source of repurposing information for tissue-aware AI approaches.Peer reviewe
Integrated network analysis reveals new genes suggesting COVID-19 chronic effects and treatment
The COVID-19 disease led to an unprecedented health emergency, still ongoing worldwide. Given the lack of a vaccine or a clear therapeutic strategy to counteract the infection as well as its secondary effects, there is currently a pressing need to generate new insights into the SARS-CoV-2 induced host response. Biomedical data can help to investigate new aspects of the COVID-19 pathogenesis, but source heterogeneity represents a major drawback and limitation. In this work, we applied data integration methods to develop a Unified Knowledge Space (UKS) and used it to identify a new set of genes associated with SARS-CoV-2 host response, both in vitro and in vivo. Functional analysis of these genes reveals possible long-term systemic effects of the infection, such as vascular remodelling and fibrosis. Finally, we identified a set of potentially relevant drugs targeting proteins involved in multiple steps of the host response to the virus.Peer reviewe
HeTriNet: Heterogeneous Graph Triplet Attention Network for Drug-Target-Disease Interaction
Modeling the interactions between drugs, targets, and diseases is paramount
in drug discovery and has significant implications for precision medicine and
personalized treatments. Current approaches frequently consider drug-target or
drug-disease interactions individually, ignoring the interdependencies among
all three entities. Within human metabolic systems, drugs interact with protein
targets in cells, influencing target activities and subsequently impacting
biological pathways to promote healthy functions and treat diseases. Moving
beyond binary relationships and exploring tighter triple relationships is
essential to understanding drugs' mechanism of action (MoAs). Moreover,
identifying the heterogeneity of drugs, targets, and diseases, along with their
distinct characteristics, is critical to model these complex interactions
appropriately. To address these challenges, we effectively model the
interconnectedness of all entities in a heterogeneous graph and develop a novel
Heterogeneous Graph Triplet Attention Network (\texttt{HeTriNet}).
\texttt{HeTriNet} introduces a novel triplet attention mechanism within this
heterogeneous graph structure. Beyond pairwise attention as the importance of
an entity for the other one, we define triplet attention to model the
importance of pairs for entities in the drug-target-disease triplet prediction
problem. Experimental results on real-world datasets show that
\texttt{HeTriNet} outperforms several baselines, demonstrating its remarkable
proficiency in uncovering novel drug-target-disease relationships.Comment: 13 pages, 3 figures, 6 table
Integrative Data Analytic Framework to Enhance Cancer Precision Medicine
With the advancement of high-throughput biotechnologies, we increasingly
accumulate biomedical data about diseases, especially cancer. There is a need
for computational models and methods to sift through, integrate, and extract
new knowledge from the diverse available data to improve the mechanistic
understanding of diseases and patient care. To uncover molecular mechanisms and
drug indications for specific cancer types, we develop an integrative framework
able to harness a wide range of diverse molecular and pan-cancer data. We show
that our approach outperforms competing methods and can identify new
associations. Furthermore, through the joint integration of data sources, our
framework can also uncover links between cancer types and molecular entities
for which no prior knowledge is available. Our new framework is flexible and
can be easily reformulated to study any biomedical problems.Comment: 18 page
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