Network controllability solutions for computational drug repurposing using genetic algorithms.

Control theory has seen recently impactful applications in network science, especially in connections with applications in network medicine. A key topic of research is that of finding minimal external interventions that offer control over the dynamics of a given network, a problem known as network controllability. We propose in this article a new solution for this problem based on genetic algorithms. We tailor our solution for applications in computational drug repurposing, seeking to maximize its use of FDA-approved drug targets in a given disease-specific protein-protein interaction network. We demonstrate our algorithm on several cancer networks and on several random networks with their edges distributed according to the Erdos-Rényi, the Scale-Free, and the Small World properties. Overall, we show that our new algorithm is more efficient in identifying relevant drug targets in a disease network, advancing the computational solutions needed for new therapeutic and drug repurposing approaches.

Network analytics for drug repurposing in COVID-19.

To better understand the potential of drug repurposing in COVID-19, we analyzed control strategies over essential host factors for SARS-CoV-2 infection. We constructed comprehensive directed protein-protein interaction (PPI) networks integrating the top-ranked host factors, the drug target proteins and directed PPI data. We analyzed the networks to identify drug targets and combinations thereof that offer efficient control over the host factors. We validated our findings against clinical studies data and bioinformatics studies. Our method offers a new insight into the molecular details of the disease and into potentially new therapy targets for it. Our approach for drug repurposing is significant beyond COVID-19 and may be applied also to other diseases.

Identification of Drug Targets in Breast Cancer Metabolic Network.

Genome-scale metabolic models have been proven to be valuable for defining cancer or to indicate the severity of cancer. However, identifying effective metabolic drug target (DT) of the active small-molecule compound is difficult to unravel and needs to be investigated. In this study, we identify effective DT for breast cancer using proposed network analysis of enzyme-centric network in the metabolic model. Our network-based analysis revealed that high degree nodes (HDNs) of enzymes are key to progression/development of cancer. These HDNs show high interconnections inside the network. It has been found that these HDNs are crucial driver nodes for effectively targeting in breast cancer metabolic network. Furthermore, based on the correlation and principal component analysis, we have shown that certain proteins play a significant role in the network and can be used as an effective DT in cancer therapeutics. In addition, these proteins stimulate the active site of enzymes to activate the target metabolites. Overall, we have shown that a better understanding of the metabolic networks using statistical model could be valuable in DT identification for developing effective therapeutic approaches and personalized medicine.

NetControl4BioMed: a pipeline for biomedical data acquisition and analysis of network controllability.

BACKGROUND: Network controllability focuses on discovering combinations of external interventions that can drive a biological system to a desired configuration. In practice, this approach translates into finding a combined multi-drug therapy in order to induce a desired response from a cell; this can lead to developments of novel therapeutic approaches for systemic diseases like cancer. RESULT: We develop a novel bioinformatics data analysis pipeline called NetControl4BioMed based on the concept of target structural control of linear networks. Our pipeline generates novel molecular interaction networks by combining pathway data from various public databases starting from the user's query. The pipeline then identifies a set of nodes that is enough to control a given, user-defined set of disease-specific essential proteins in the network, i.e., it is able to induce a change in their configuration from any initial state to any final state. We provide both the source code of the pipeline as well as an online web-service based on this pipeline http://combio.abo.fi/nc/net_control/remote_call.php . CONCLUSION: The pipeline can be used by researchers for controlling and better understanding of molecular interaction networks through combinatorial multi-drug therapies, for more efficient therapeutic approaches and personalised medicine.

Structural Target Controllability of Linear Networks.

Computational analysis of the structure of intra-cellular molecular interaction networks can suggest novel therapeutic approaches for systemic diseases like cancer. Recent research in the area of network science has shown that network control theory can be a powerful tool in the understanding and manipulation of such bio-medical networks. In 2011, Liu et al. developed a polynomial time algorithm computing the size of the minimal set of nodes controlling a linear network. In 2014, Gao et al. generalized the problem for target control, minimizing the set of nodes controlling a target within a linear network. The authors developed a Greedy approximation algorithm while leaving open the complexity of the optimization problem. We prove here that the target controllability problem is NP-hard in all practical setups, i.e., when the control power of any individual input is bounded by some constant. We also show that the algorithm provided by Gao et al. fails to provide a valid solution in some special cases, and an additional validation step is required. We fix and improve their algorithm using several heuristics, obtaining in the end an up to 10-fold decrease in running time and also a decrease in the size of solutions.

Controlling Directed Protein Interaction Networks in Cancer.

Control theory is a well-established approach in network science, with applications in bio-medicine and cancer research. We build on recent results for structural controllability of directed networks, which identifies a set of driver nodes able to control an a-priori defined part of the network. We develop a novel and efficient approach for the (targeted) structural controllability of cancer networks and demonstrate it for the analysis of breast, pancreatic, and ovarian cancer. We build in each case a protein-protein interaction network and focus on the survivability-essential proteins specific to each cancer type. We show that these essential proteins are efficiently controllable from a relatively small computable set of driver nodes. Moreover, we adjust the method to find the driver nodes among FDA-approved drug-target nodes. We find that, while many of the drugs acting on the driver nodes are part of known cancer therapies, some of them are not used for the cancer types analyzed here; some drug-target driver nodes identified by our algorithms are not known to be used in any cancer therapy. Overall we show that a better understanding of the control dynamics of cancer through computational modelling can pave the way for new efficient therapeutic approaches and personalized medicine.

Network Topologies Decoding Cervical Cancer.

According to the GLOBOCAN statistics, cervical cancer is one of the leading causes of death among women worldwide. It is found to be gradually increasing in the younger population, specifically in the developing countries. We analyzed the protein-protein interaction networks of the uterine cervix cells for the normal and disease states. It was found that the disease network was less random than the normal one, providing an insight into the change in complexity of the underlying network in disease state. The study also portrayed that, the disease state has faster signal processing as the diameter of the underlying network was very close to its corresponding random control. This may be a reason for the normal cells to change into malignant state. Further, the analysis revealed VEGFA and IL-6 proteins as the distinctly high degree nodes in the disease network, which are known to manifest a major contribution in promoting cervical cancer. Our analysis, being time proficient and cost effective, provides a direction for developing novel drugs, therapeutic targets and biomarkers by identifying specific interaction patterns, that have structural importance.