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Open Access Publications from the University of California

Scholarly Works (16 results)

  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2019)
Multitarget pharmacology of small-molecule cancer drugs significantly contributes to their mechanism of action, side effects, and emergence of drug resistance and opens ways to repurpose, combine, or customize drug therapy. In most cases, the set of targets affected at therapeutic concentrations is not fully characterized and/or the interaction efficacy values are not accurately quantified. We collected information about multiple targets for each cancer drug along with their experimental effective concentrations or binding activities from multiple sources. All multitarget activity values for each drug then were used to build two proximity network pharmacology maps of anticancer drugs and targets of those drugs, respectively. Together with the network map, we showed that the majority of the cancer drugs had substantial multitarget pharmacology based on our current knowledge. In addition, most of the cancer drugs simultaneously affect macromolecular targets from different classes and types. The target subset can further be accentuated and personalized by patient sample-specific expression data. The network maps of cancer drugs and targets as well as all quantified activity data were integrated into a freely available database, CancerDrugMap (http://ruben.ucsd.edu/dnet/maps/drugnet.html). The identified multitarget pharmacology of cancer drugs is essential for improving the efficacy of individually prescribed drugs and drug combinations and minimization of adverse effects.
    Cover page: Extended Multitarget Pharmacology of Anticancer Drugs
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2020)

    This dissertation describes studies into a new drug candidate discovery philosophy and its application to diseases. Over the last several decades, drug discovery has been focusing on one single target modulation. However, due to the high failure rate in drug development, a new philosophy that focusing on multiple drug-target interactions has gained escalating attention in both academia and industry. In this philosophy, drugs, especially

    small-molecule drugs interact with multiple protein targets in their therapeutic concentrations.

    In chapter 1, we explored the multi-target pharmacology of cancer drugs. We collected information about multiple targets for each cancer drug along with their experimental effective concentrations or binding activities from multiple sources. We showed that the majority of the cancer drugs had substantial multi-target pharmacology based on our current knowledge. The target subset can further be accentuated and personalized by patient sample-specific expression data. Besides analysis, we also built a web database for the public to access and easily explore the multi-target pharmacology of cancer drugs.

    To gain a comprehensive multi-target pharmacology, we still need to study new protein targets to further extend the collection of known targets. In chapters 2 and 3, we studied a bacterial transcription factor, RfaH, which may be developed into a new antibacterial target. RfaH is a transcription processivity factor, belonging to a universally conserved transcriptional regulator, NusG/Stp5 family. Unlike other family members, RfaH exerts a distinct structural transformation during its binding to RNA polymerase. We first identified two key residues for the structural transformation through a combined structural and phylogenetic analysis. Then we screened a compound library and identified 3 first-in-class inhibitors for RfaH binding to RNA polymerase.

    In chapter 4, we developed a novel target for Naegleria fowleri infection, primary amoebic meningoencephalitis (PAM). PAM is a rapid-onset brain infection in humans with over 97% mortality rate. Despite some progress in the treatment of the disease, there is no single, proven, evidence-based treatment with a high probability of cure. The target we developed was ERG2, an isomerase in the ergosterol synthetic pathway. We built a homology model of ERG2 and identified 4 amoebicidal chemicals with low human cell toxicity.

      Cover page: Multi-target pharmacology of small molecule drugs and first-in-class inhibitors discovery
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2019)
      In nearly 50% of patients with drug-induced liver injury, the bile flow is impaired known as cholestasis. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease that happens in pregnancy. Some of the clinical symptoms include pruritus, dark urine, and abnormal liver function tests. A rise of serum bile acids is the most accurate diagnostic evidence. ICP may lead to premature birth, fetal distress, and even postpartum hemorrhage or stillbirth in some severe cases. Higher bile acid levels (> 40 μmol/L) are associated with higher rates of adverse fetal outcomes. Due to the multifactorial nature of ICP, its etiology is still not fully understood. Therefore, the current treatments of ICP are limited to control symptoms and protect fetuses. Among various causing factors, drug exposure during pregnancy is one common factor, and it can be prevented if we know drugs with increasing risk of cholestasis. Here we analyzed over 9.5 million FDA adverse effect reports to identify drugs with increasing risks of cholestasis as an adverse effect. Patients treated for cholestasis or liver diseases were removed. The odds ratio analysis reveals that lansoprazole (LSPZ), omeprazole (OMPZ) and amoxicillin (AMXC) are associated with an increased risk of cholestasis. LSPZ is associated with increased reported cholestasis by a factor of 2.32 (OR with 95% confidence interval [2.21, 2.43]). OMPZ is associated with increased reported cholestasis by a factor of 2.61 [2.54, 2.69]. AMXC is associated with increased reported cholestasis adverse effect by a factor of 6.79 [6.49, 7.11]. The risk of cholestasis associated with these three drugs is further increased in pregnant women. These findings justify careful reassessment of the safety of the three identified drugs.
        Cover page: Population Scale Retrospective Analysis Reveals Potential Risk of Cholestasis in Pregnant Women Taking Omeprazole, Lansoprazole, and Amoxicillin
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2017)
        Transcription factors from the NusG family bind to the elongating RNA polymerase to enable synthesis of long RNAs in all domains of life. In bacteria, NusG frequently co-exists with specialized paralogs that regulate expression of a small set of targets, many of which encode virulence factors. Escherichia coli RfaH is the exemplar of this regulatory mechanism. In contrast to NusG, which freely binds to RNA polymerase, RfaH exists in a structurally distinct autoinhibitory state in which the RNA polymerase-binding site is buried at the interface between two RfaH domains. Binding to an ops DNA sequence triggers structural transformation wherein the domains dissociate and RfaH refolds into a NusG-like structure. Formation of the autoinhibitory state, and thus sequence-specific recruitment, represents the decisive step in the evolutionary history of the RfaH subfamily. We used computational and experimental approaches to identify the residues that confer the unique regulatory properties of RfaH. Our analysis highlighted highly conserved Ile and Phe residues at the RfaH interdomain interface. Replacement of these residues with equally conserved Glu and Val counterpart residues in NusG destabilized interactions between the RfaH domains and allowed sequence-independent recruitment to RNA polymerase, suggesting a plausible pathway for diversification of NusG paralogs.
          Cover page: Flipping states: a few key residues decide the winning conformation of the only universally conserved transcription factor
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2018)
          RfaH is required for virulence in several Gram-negative pathogens including Escherichia coli and Klebsiella pneumoniae. Through direct interactions with RNA polymerase (RNAP) and ribosome, RfaH activates the expression of capsule, cell wall and pilus biosynthesis operons by reducing transcription termination and activating translation. While E. coli RfaH has been extensively studied using structural and biochemical approaches, limited data are available for other RfaH homologs. Here we set out to identify small molecule inhibitors of E. coli and K. pneumoniae RfaHs. Results of biochemical and functional assays show that these proteins act similarly, with a notable difference between their interactions with the RNAP β subunit gate loop. We focused on high-affinity RfaH interactions with the RNAP β' subunit clamp helices as a shared target for inhibition. Among the top 10 leads identified by in silico docking using ZINC database, 3 ligands were able to inhibit E. coli RfaH recruitment in vitro. The most potent lead was active against both E. coli and K. pneumoniae RfaHs in vitro. Our results demonstrate the feasibility of identifying RfaH inhibitors using in silico docking and pave the way for rational design of antivirulence therapeutics against antibiotic-resistant pathogens.
            Cover page: In silico discovery of small molecules that inhibit RfaH recruitment to RNA polymerase
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2014)
            Anodic alumina with surface of hexagonal patterned nanodots was prepared by a two-step anodizing procedure. Scanning electron microscope and atomic force microscopy results clearly showed the formation of self-organized hexagonal patterned nanostructure. Diameters of the nanodots were controlled by choosing different anodization voltage and types of electrolyte acids. Co/Pt multilayers deposited on the nanodots with different diameters of 20, 70, and 100 nm lead to the formation of magnetic nanostructures with perpendicular anisotropy. Magnetometry and the first-order reversal curve method were used to study the magnetic properties of Co/Pt nanostructures. An out-of-plane magnetic easy axis was observed for the continuous films and the nanodots with diameters of 100 and 70 nm. The magnetic multilayers deposited on 20 nm nanodots appeared to have taken on a hard axis type behavior. The curvature of nanodot arrays induces strong modifications on the magnetic properties of the nanostructures.
              Cover page: Co/Pt Multilayers on Self-Organized Hexagonal Patterned Nanodots
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2021)
              Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, a long treatment course, and the need for an additional drug to prevent cyst-mediated transmission. E. histolytica possesses a kinome with approximately 300-400 members, some of which have been previously studied as potential targets for the development of amoebicidal drug candidates. However, while these efforts have uncovered novel potent inhibitors of E. histolytica kinases, none have resulted in approved drugs. In this study we took the alternative approach of testing a set of twelve previously FDA-approved antineoplastic kinase inhibitors against E. histolytica trophozoites in vitro. This resulted in the identification of dasatinib, bosutinib, and ibrutinib as amoebicidal agents at low-micromolar concentrations. Next, we utilized a recently developed computational tool to identify twelve additional drugs with human protein target profiles similar to the three initial hits. Testing of these additional twelve drugs led to the identification of ponatinib, neratinib, and olmutinib were identified as highly potent, with EC50 values in the sub-micromolar range. All of these six drugs were found to kill E. histolytica trophozoites as rapidly as metronidazole. Furthermore, ibrutinib was found to kill the transmissible cyst stage of the model organism E. invadens. Ibrutinib thus possesses both amoebicidal and cysticidal properties, in contrast to all drugs used in the current therapeutic strategy. These findings together reveal antineoplastic kinase inhibitors as a highly promising class of potent drugs against this widespread and devastating disease.
                Cover page: Antineoplastic kinase inhibitors: A new class of potent anti-amoebic compounds
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2020)
                The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a "logical" statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent "brute force" approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which "multispecific" kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug-metabolite interactions.
                  Cover page: Unique metabolite preferences of the drug transporters OAT1 and OAT3 analyzed by machine learning
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2020)
                  The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as "drug" transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.
                    Cover page: Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2022)
                    Integration of multi-omics data with molecular interaction networks enables elucidation of the pathophysiology of Alzheimer's disease (AD). Using the latest genome-wide association studies (GWAS) including proxy cases and the STRING interactome, we identified an AD network of 142 risk genes and 646 network-proximal genes, many of which were linked to synaptic functions annotated by mouse knockout data. The proximal genes were confirmed to be enriched in a replication GWAS of autopsy-documented cases. By integrating the AD gene network with transcriptomic data of AD and healthy temporal cortices, we identified 17 gene clusters of pathways, such as up-regulated complement activation and lipid metabolism, down-regulated cholinergic activity, and dysregulated RNA metabolism and proteostasis. The relationships among these pathways were further organized by a hierarchy of the AD network pinpointing major parent nodes in graph structure including endocytosis and immune reaction. Control analyses were performed using transcriptomics from cerebellum and a brain-specific interactome. Further integration with cell-specific RNA sequencing data demonstrated genes in our clusters of immunoregulation and complement activation were highly expressed in microglia.
                      Cover page: Mapping the gene network landscape of Alzheimer’s disease through integrating genomics and transcriptomics
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