AI Enabled Drug Design and Side Effect Prediction Powered by Multi-Objective Evolutionary Algorithms & Transformer Models

Due to the large search space and conflicting objectives, drug design and discovery is a difficult problem for which new machine learning (ML) approaches are required. Here, the problem is to invent a method by which new, therapeutically useful, compounds can be discovered; and to simultaneously avoid compounds which will fail clinical trials or pass unwanted effects onto the end patient. By extending current technologies as well as adding new ones, more design criteria can be included, and more promising novel drugs can be discovered. This work advances the field of computational drug design by (1) developing MOEA-DT, a non-deep learning application for multi-objective molecular optimization, which generates new molecules with high performance in a variety of design criteria; and (2) developing SEMTL-BERT, a side effect prediction algorithm which leverages the latest ML techniques and datasets to accomplish its task. Experiments performed show that MOEA-DT either matches or outperforms other similar methods, and that SEMTL-BERT can enhance predictive ability

ANTICANCER ACTIVITIES OF THIOSEMICARBAZIDES/THIOSEMICARBAZONES: A REVIEW

There have been tremendous development in the chemotherapy of cancer and researches are still developing new and more effective drugs to combat this disease. Thiosemicarbazides and thiosemicarbazone possess a wide range of biological applications. This key biological role is often related with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is observed with potent anticancer drugs such as triapine and methisazone. Recent studies have revealed that thiosemicarbazones can inhibit topoisomerase II enzyme. This review discusses current advances of an emerging ‘new wave' of thiosemicarbazide/thiosemicarbazone and their metal complexes as potent anticancer agents, mode of action and toxicity caused by them

Gastrointestinal viruses and beyond: antiviral development and molecular epidemiology

With over 27 viral families known to infect humans, viral pathogens impose a significant global public health and economic burden. Despite this, only a small fraction of human viruses possess antiviral treatments or vaccines. Whilst antiviral development efforts are crucial to the host-pathogen arms race, so too is the molecular surveillance of these viruses to identify prevalent and virulent strains for vaccine development. This thesis begins, in chapter four, with the development of broad-spectrum non-nucleoside inhibitor compounds using a complex-based pharmacophore and virtual screening approach. This virtual screen identified one compound, NCS-013, which demonstrated broad-spectrum inhibition of the transcriptional activity of human norovirus and feline calicivirus from the Caliciviridae, Zika virus and hepatitis C virus from the Flaviviridae and hepatitis A virus from the Picornaviridae. The second half of the thesis focuses on molecular epidemiology of norovirus and adenovirus, two of the leading causes of viral gastroenteritis worldwide. In chapter five, we observed an interesting dynamic of GII.4 Sydney 2012 [P16] co-dominance in clinical samples throughout the study period. We also enhanced our sewage surveillance capabilities through the addition of partial ORF1 sequencing enabling the identification of recombinant strains. The role of non-group F adenoviruses in gastroenteritis although often reported, remains an area of controversy. In chapter six, we analysed sewage to complement clinical samples and better understand the diversity of adenovirus within the population, including from healthy individuals. In summary, this thesis approached the problem of viral pathogens from both the angle of antiviral development and through understanding of population-level molecular epidemiology, which can contribute to future vaccine development efforts

Synthesis of novel high-affinity FimH antagonists with improved pharmacokinetic properties

Urinary tract infections (UTIs) belong to the most common bacterial infections worldwide. Uropathogenic Escherichia coli (UPEC) are held accountable for majority of the cases. Millions of people suffer from UTI each year, with the highest incidence rate reported among women. Moreover, woman once affected will most likely experience a recurrent infection. High prevalence and recurrence of UTI lead to considerable medical costs. The current treatment generally involves antibiotics. However, choosing a proper antibiotic therapy becomes more difficult as resistant strains rapidly proliferate. Therefore, the need to develop alternative, non-antibiotic strategies is more pressing than ever. UPEC express filamentous organelles called type 1 pili (fimbriae), which protrude from the bacterial surface and mediate the adhesion to the bladder-epithelial cells. The mannose-specific adhesin FimH is located on the distal end of the pili. It contains the mannose-specific carbohydrate recognition domain (CRD), which binds to highly mannosylated uroplakin 1a (UP1a) expressed by urothelial cells leading to the infection. The compounds capable of blocking the interaction between FimH and surface-exposed glycans pave the way for a novel anti-adhesive strategy to treat and prevent UTI. The first part of the thesis addresses the problem of poor oral bioavailability arising from high polarity of the FimH antagonists. The strategy involves a prodrug approach, in which lipophilic esters are introduced to the parent compounds either on the aglycone’s carboxylic acid or the mannose moiety. The absorption potential as well as propensity to hydrolysis by esterases of liver or plasma was evaluated. The second part of the thesis emphasizes the optimization of the pharmacodynamic properties of FimH antagonists. In the first approach, the mannose moiety was modified in order to explore a cavity located at the entrance to binding pocket. The obtained antagonists were evaluated in competitive binding assay and by isothermal titration calorimetry (ITC) to reveal their thermodynamic binding profile. The second approach involved an elongation of the aglycone to allow additional interactions with the guanidinium side chain of Arg98. For the evaluation of these antagonists, competitive binding assays with the wild type FimH and the R98A mutant was established

Acid-sensing ion channel 3: An analgesic target.

Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily. There are 7 different ASIC subunits encoded by 5 different genes. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo- and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC3 can encode prolonged acidosis as a nociceptive signal. Furthermore, certain mediators sensitize ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions.Work in the Smith Lab is supported by Versus Arthritis Research Grant (RG21973) and Biotechnology and Biological Sciences Research Council grant (BB/R006210/1)

Lectins as drug targets : functional, structural, and pharmacological insights into E-selectin and FimH

Lectins are carbohydrate-binding proteins found throughout nature in plants, viruses, pro- and eukaryotes. Their carbohydrate specificity as well as their biological functions are highly diverse. Lectins in humans primarily serve as cell-surface receptors and are mainly involved in the immunogenic processes. Bacterial lectins are often involved in conferring pathogenesis by binding to carbohydrates of the host. In this thesis, structural, functional, and pharmacological insights on the mammalian lectin E-selectin and the bacterial lectin FimH are given. Part E-selectin: E-selectin is a C-type lectin involved in leukocyte recruitment during inflammation by binding to the tetrasaccharide ligand sialyl Lewisx (sLex). It is involved in numerous diseases, e.g. asthma, psoriasis, stroke, rheumatoid arthritis or cancer metastasis. Targeting E-selectin with glycomimetic antagonists is therefore in the focus of drug discovery. The following aspects of E-selectin were investigated: -Publication 1: The thermodynamic driving forces of the interaction of E-selectin with sLex and glycomimetics thereof were investigated. We demonstrated that sLex binding is an entropy-driven process, which is an uncommon feature of carbohydrate-lectin interactions. -Manuscript 1: The co-crystallization of E-selectin with sLex or a more potent glycomimetics thereof revealed a previously unseen induced fit of the binding site involving alterations in the first two domains. We showed that this induced fit occurs in solution and discuss the physiological relevance. -Manuscript 2: A flexible and a pre-organized E-selectin antagonist were characterized for their kinetic and thermodynamic properties, which revealed an unexpected loss in entropy for the pre-organized antagonist. Co-crystallization with a series of antagonists revealed the reason for this behavior. -Publication 2: The single nucleotide polymorphism which leads to the S128R mutation in E-selectin has been correlated with an increased risk of developing various diseases. We investigated the binding behavior of this mutant and demonstrated that glycomimetics are efficacious in inhibiting E-selectin-S128R mediated binding. -Manuscript 3: Mice are able to express the N-glycolyl form of sLex, unlike humans. Therefore, the specificity of murine E-selectin might be altered. We investigated the binding specificity of murine E-selectin and evaluated the potency of antagonists designed for human E-selectin. We confirmed the efficacy of E-selectin antagonists towards murine E-selectin, thus demonstrating the validity of mouse models. Part FimH: The bacterial lectin FimH is presented by uropathogenic E. coli (UPEC) on the tip of type 1 pili and mediates the adhesion to mannosylated structure in the lower urinary tract. This interaction allows UPEC to colonize the bladder, the initial step in bladder infection. Mannoside-based FimH antagonists are under investigation as treatment for bladder infections. -Manuscript 4: The goal of a drug discovery program aimed to develop a treatment for urinary tract infections is to identify high-affinity, orally available, and safe FimH antagonists. Starting from the carboxylate substituted biphenyl alpha-D-mannopyranoside, affinity as well as the relevant pharmacokinetic parameters (solubility, permeability, renal excretion) could be substantially improved by a bioisosteric approach. -Manuscript 5: To comprehend and further develop potent FimH antagonists, structural data on ligand-protein interaction is essential. In this manuscript we present the X-ray co-crystal structures of FimH with three antagonist classes for which structural data were unavailable to date and provide an explanation for the observed entropy-enthalpy compensation by NMR. -Manuscript 6: Crystallographic studies of FimH with alkyl- or aryl-substituted alpha-D-mannopyranosides have demonstrated alternative binding poses with differing involvement of the residues Tyr48 and Tyr137 at the binding site entrance. Thermodynamic and molecular modeling analysis provided insights into the importance of the tyrosine-gate. -Manuscript 7: Several mutations of FimH are found in clinical isolates, which influence the binding phenotype of FimH by altering the interaction of the two FimH domains (lectin- and pilin domain). To date, FimH antagonists have never been tested on clinically relevant FimH variants. We demonstrated that antagonist affinity correlated with the binding behavior of different FimH variants

Translational Research in Cancer

Translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies concerning the molecular pathways involved in tumorigenesis. Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. The vast majority of cancer cases are due to environmental risk factors. Many of these environmental factors are controllable lifestyle choices. Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to the best existing treatment through translational research. The key features of the book include: 1) New screening for the development of radioprotectors: radioprotection and anti-cancer effect of β-Glucan (Enterococcus faecalis) 2) Translational perspective on hepatocellular carcinoma 3) Brachytherapy for endometrial cancer 4) Discovery of small molecule inhibitors for histone methyltransferases in cance

In silico identification and characterization of Kaurene Synthase protein in Stevia rebaudiana MS007

Stevia rebaudiana (Sr), belonging to Asteraceae family is a plant native to Paraguay. It is currently being used as a healthier alternative for sugar. Sr produces steviol glycosides (SGs), a group of secondary metabolite compounds that is responsible for its sweetening taste. SGs act as sweetener due to the presence of two major compounds, Stevioside and Rebaudioside A. Biosynthesis of these compounds involve enzymes such as geranylgeranyl pyrophosphate (GPPS), copalyl diphosphate synthase (CPPS), kaurene synthase (KS) and kaurene oxidase (KO) in the pathway. In this study, the identification and characterization of Stevia rebaudiana MS007 kaurene synthase (SrKS) were done by in silico analysis of the transcriptomic dataset. Homology search from BLASTx resulting in SrKSfrom query Cluster-31069.42907 (Sr MS007) of transcriptomic dataset shows the highest similarity percentage identity (99.62%). ExPasy tools were used to translate the nucleotide sequence into protein sequence. The protein domain is predicted by protein domain search analysis using Interpro and shows IPR005630 (terpene synthase metal-binding domain) available at positions 454 to 719 and IPR001906 (terpene-synthase-N-terminal-domain) at position 222 to 411 as the domains. In constructing the phylogenetic analysis tree, multiple sequence alignment was initially done using MUSCLE and MEGA-X was used as phylogenetic tree analysis tools. Cluster-31069.42907 shows the relationship between the ancestors, based on the bootstrap value. Bootstrap value of Helianthus annuus and Stevia rebaudiana is 100% as both the sequences are from the Asteraceae family. This study contributes to a deeper understanding of S. rebaudiana MS007 Kaurene synthase through in silico analysis