Anticancer and antibiotic leads from marine organis

During the past three decades, the development of marine natural products as drug leads has become a promising avenue for research. As our efforts towards the discovery of anticancer and antibiotic drug leads from marine organisms, modifications of anticancer drug candidate kahalalide F, isolations of new peptides from the mollusk, Elysia rufescens and anticancer drug leads from the NCI repository, as well as chemical regulation of antibiotic production from marine Pseudomonas aeruginosa were investigated. Kahalalide F (KF) is a potent anticancer lead isolated from the herbivorous marine mollusk E. rufescens and its algal diet Bryopsis pennata. Our semisynthesis approach was aimed to improve the efficacy or prolong the half-life resulted in 15 KF analogues. These analogues included eight elongation products with nonpolar amino acid residues, four analogues with modified amino group at the Orn residue, one dehydration product of KF, and two new cyclization products of kahalalide G. All the analogues are being evaluated by Wayne State University for solid tumor cytotoxicity. In the course of the isolation of KF as starting material for its analogues, nine new and 10 known peptides were isolated from E. rufescens. However, only five structures were determined and the remaining four structures could not be assigned due to limited sample amounts (less than 1 mg). Future work will focus on the structure assignment using FTMS amino acid sequence analysis or 700 MHz NMR. During the screening of anticancer drug leads from the NCI repository, 27 extracts from marine organisms were tested, and 12 known compounds including tetracyclic aromatic alkaloids, diterpenoids and pyrroloaminopropylimidazole alkaloids were purified. Bioassay-guided isolation from marine P. aeruginosa collected in the Gulf of Mexico afforded 15 known antibiotics including two phenazines, six 2-alkyl-4-quinolones, and seven rhamnolipids. 2-Nonyl-4(1H)-quinolone and 2-(1-nonenyl)-4(1H)-quinolone displayed potent antimalarial activity, which was first reported here. Based on the metabolic profile of antibiotics from P. aeruginosa, chemical regulation and its impact on the yield of these metabolites were investigated. Treatment of P. aeruginosa with sceptrin and co-culturing with another Pseudomonas sp. increased antibiotic production significantly. This could be attributed to the activation of antibiotic biosynthetic gene expression under stress conditions

The effects of combinatorial chemistry and technologies on drug discovery and biotechnology : A mini review

The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of "combinatorial thinking" in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided

Exploiting multiple hit-identification strategies to identify novel inhibitors of the anti-infective target DXPS

The coronavirus pandemic has raised awareness for infectious diseases, which also put a spotlight on the fight against anti-microbial resistance. A promising new target in this fight is 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). Although it has been known for the past few decades, only a few promising inhibitors have been identified so far. For this thesis, multiple hit-identification strategies were pursued with a special focus on Mycobacterium tuberculosis and Plasmodium falciparum DXPS to find new inhibitors. For this thesis a focused fragment library was screened against DXPS in different biophysical assay, in collaboration with the company Atomwise, a virtual screening was performed and three previously identified hit classes were investigated in phenotypic assays against P. falciparum and synthetically optimized. In summary, this thesis has contributed to the identification of several new binders and inhibitors that have promising properties to continue their optimization into leads for drug development.Die Corona Pandemie hat dafür gesorgt, dass Infektionskrankheiten und damit auch der Kampf gegen antibiotikaresistente Keime ins Bewusstsein der Öffentlichkeit gerückt sind. Ein neues Target in diesem Kampf ist die 1-Deoxy-D-xylulose-5-phosphat Synthase (DXPS). Das Enzym ist bereits seit einigen Jahrzehnten bekannt, aber bisher wurden nur wenige Inhibitoren gefunden. In dieser Arbeit wurden verschiedene Hit-Identifikationsstrategien genutzt, um neue Inhibitoren gegen Mycobacterium tuberculosis und Plasmodium falciparum DXPS zu finden. Dafür wurde eine fokussierte Fragmentbibliothek gegen DXPS in verschiedenen biophysikalischen Assays untersucht, ein HPLC-MS/MS-basierter DXPS Assay wurde etabliert, in Kooperation mit der Firma Atomwise wurde ein virtuelles Screening an DXPS durchgeführt und drei bereits bekannte Hit-Klassen wurden im Rahmen dieser Arbeit in phänotypischen Assays gegen P. falciparum getestet und synthetisch optimiert. Zusammengefasst hat diese Arbeit zur Identifikation mehrerer Binder und Inhibitoren beigetragen, die vielversprechende Eigenschaften aufweisen und weiter zu Lead-Verbindungen optimiert und somit für die Medikamentenentwicklung genutzt werden können

Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

Thymidine monophosphate kinase (TMPK(mt)) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2',3'-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2',3'-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPK(mt) binding site. The three-dimensional structure of the TMPK(mt) complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPK(mt) target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties

IN SILICO METHODS FOR DRUG DESIGN AND DISCOVERY

Computer-aided drug design (CADD) methodologies are playing an ever-increasing role in drug discovery that are critical in the cost-effective identification of promising drug candidates. These computational methods are relevant in limiting the use of animal models in pharmacological research, for aiding the rational design of novel and safe drug candidates, and for repositioning marketed drugs, supporting medicinal chemists and pharmacologists during the drug discovery trajectory.Within this field of research, we launched a Research Topic in Frontiers in Chemistry in March 2019 entitled “In silico Methods for Drug Design and Discovery,” which involved two sections of the journal: Medicinal and Pharmaceutical Chemistry and Theoretical and Computational Chemistry. For the reasons mentioned, this Research Topic attracted the attention of scientists and received a large number of submitted manuscripts. Among them 27 Original Research articles, five Review articles, and two Perspective articles have been published within the Research Topic. The Original Research articles cover most of the topics in CADD, reporting advanced in silico methods in drug discovery, while the Review articles offer a point of view of some computer-driven techniques applied to drug research. Finally, the Perspective articles provide a vision of specific computational approaches with an outlook in the modern era of CADD