Web-based 3D-visualization of the DrugBank chemical space

BACKGROUND Similarly to the periodic table for elements, chemical space offers an organizing principle for representing the diversity of organic molecules, usually in the form of multi-dimensional property spaces that are subjected to dimensionality reduction methods to obtain 3D-spaces or 2D-maps suitable for visual inspection. Unfortunately, tools to look at chemical space on the internet are currently very limited. RESULTS Herein we present webDrugCS, a web application freely available at www.gdb.unibe.ch to visualize DrugBank (www.drugbank.ca, containing over 6000 investigational and approved drugs) in five different property spaces. WebDrugCS displays 3D-clouds of color-coded grid points representing molecules, whose structural formula is displayed on mouse over with an option to link to the corresponding molecule page at the DrugBank website. The 3D-clouds are obtained by principal component analysis of high dimensional property spaces describing constitution and topology (42D molecular quantum numbers MQN), structural features (34D SMILES fingerprint SMIfp), molecular shape (20D atom pair fingerprint APfp), pharmacophores (55D atom category extended atom pair fingerprint Xfp) and substructures (1024D binary substructure fingerprint Sfp). User defined molecules can be uploaded as SMILES lists and displayed together with DrugBank. In contrast to 2D-maps where many compounds fold onto each other, these 3D-spaces have a comparable resolution to their parent high-dimensional chemical space. CONCLUSION To the best of our knowledge webDrugCS is the first publicly available web tool for interactive visualization and exploration of the DrugBank chemical space in 3D. WebDrugCS works on computers, tablets and phones, and facilitates the visual exploration of DrugBank to rapidly learn about the structural diversity of small molecule drugs.Graphical abstractwebDrugCS visualization of DrugBank projected in 3D MQN space color-coded by ring count, with pointer showing the drug 5-fluorouracil

Exploring Structural Diversity of Microbe Secondary Metabolites Using OSMAC Strategy: A Literature Review

Microbial secondary metabolites (MSMs) have played and continue to play a highly significant role in the drug discovery and development process. Genetically, MSM chemical structures are biologically synthesized by microbial gene clusters. Recently, however, the speed of new bioactive MSM discovery has been slowing down due to consistent employment of conventional cultivation and isolation procedure. In order to alleviate this challenge, a number of new approaches have been developed. The strategy of one strain many compounds (OSMAC) has been shown as a simple and powerful tool that can activate many silent biogenetic gene clusters in microorganisms to make more natural products. This review highlights important and successful examples using OSMAC approaches, which covers changing medium composition and cultivation status, co-cultivation with other strain(s), adding enzyme inhibitor(s) and MSM biosynthetic precursor(s). Available evidences had shown that variation of cultivation condition is the most effective way to produce more MSMs and facilitate the discovery of new therapeutic agents

Cheminformatics Tools to Explore the Chemical Space of Peptides and Natural Products

Cheminformatics facilitates the analysis, storage, and collection of large quantities of chemical data, such as molecular structures and molecules' properties and biological activity, and it has revolutionized medicinal chemistry for small molecules. However, its application to larger molecules is still underrepresented. This thesis work attempts to fill this gap and extend the cheminformatics approach towards large molecules and peptides. This thesis is divided into two parts. The first part presents the implementation and application of two new molecular descriptors: macromolecule extended atom pair fingerprint (MXFP) and MinHashed atom pair fingerprint of radius 2 (MAP4). MXFP is an atom pair fingerprint suitable for large molecules, and here, it is used to explore the chemical space of non-Lipinski molecules within the widely used PubChem and ChEMBL databases. MAP4 is a MinHashed hybrid of substructure and atom pair fingerprints suitable for encoding small and large molecules. MAP4 is first benchmarked against commonly used atom pairs and substructure fingerprints, and then it is used to investigate the chemical space of microbial and plants natural products with the aid of machine learning and chemical space mapping. The second part of the thesis focuses on peptides, and it is introduced by a review chapter on approaches to discover novel peptide structures and describing the known peptide chemical space. Then, a genetic algorithm that uses MXFP in its fitness function is described and challenged to generate peptide analogs of peptidic or non-peptidic queries. Finally, supervised and unsupervised machine learning is used to generate novel antimicrobial and non-hemolytic peptide sequences

Synthèse et relations structure-activité cytotoxique et antibactérienne des dirchromones

L’exploration de l’espace chimique biologiquement pertinent requiert l’utilisation de règles ou de sources d’inspiration permettant de circonscrire les recherches au sein de l’immensité des assemblages possibles des atomes de carbone. Parmi ces stratégies, l’examen de substances d’origine naturelle conserve une place de choix, tant parce qu’elles fournissent des pistes qui auraient été difficilement accessibles par synthèse classique que parce qu’elles sont le résultat de coévolution de formes de vie les sécrétant précisément pour influencer d’autres organismes. Antérieurement, l’étude de l’arbuste Dirca palustris a permis d’y découvrir une famille de molécules soufrées, les dirchromones, présentant des activités cytotoxique et antibactérienne contre Staphylococcus aureus. Leur chaîne latérale comportant un vinylsulfoxyde les classe à l’écart des autres chromones végétales et leur fait donc couvrir une nouvelle niche de l’espace chimique. Cependant, leur faible abondance dans la plante ne permettait pas d’aller au-delà de leur simple catalogage. Dans le cadre de cette thèse, trois objectifs étaient donc poursuivis: développer une voie de synthèse de la dirchromone qui soit à la fois accessible, flexible et économe en étapes; déterminer la ou les caractéristiques structurales les plus critiques pour les activités biologiques; et explorer les relations entre des modifications structurales systématiques et les activités cytotoxique et antibactérienne. Dans un premier temps, une synthèse totale des dirchromones a été développée afin de contourner les écueils rencontrés par des approches classiques, avec comme étapes clé un réarrangement de Pummerer de transfert d’oxydation inusité et le premier exemple de réarrangement de Baker-Venkataraman en conditions d’énolisation douce rapporté dans la littérature. La démarche complète comporte sept étapes ayant permis de préparer la dirchromone à l’échelle du gramme avec un rendement global de 21 % à partir de réactifs facilement accessibles. Cette même synthèse s’est avérée adaptable, permettant d’introduire des substituants à de nombreuses positions du squelette et également de préparer d’autres chromones courantes. À ce stade, la cytotoxicité de la dirchromone synthétique a été validée sur 13 lignées cellulaires cancéreuses. En second lieu, mettant à profit cette synthèse, différentes modifications structurales ont été introduites sur le fragment moléculaire rendant la dirchromone unique, à savoir sa chaîne latérale soufrée. Il en ressort notamment que le degré d’oxydation du soufre est capital à l’expression de ses activités biologiques, le sulfoxyde étant plus cytotoxique alors que la sulfone est plus antibactérienne et le sulfide inactif dans les deux cas. Afin de mieux comprendre l’implication de la chaîne latérale sur la réactivité de la dirchromone, cette dernière a été soumise à un test pour mesurer son caractère d’accepteur de Michael par une réaction avec de la cystéamine suivie par résonnance magnétique nucléaire. Devant le comportement surprenant observé, les produits de la réaction ont été caractérisés, mettant en évidence une séquence de réactions combinant une addition de Michael, une élimination du fragment méthylsulfinyl et des conversions oxydoréductrices. La fluorescence de certains de ces produits a également permis de mettre en évidence l’occurrence de réactions similaires au sein du cytosol de cellules traitées avec la dirchromone. Troisièmement, 32 analogues de la dirchromone présentant différents substituants (méthylations, hétéroatomes, acylations et alkoxydations avec différentes longueurs et ramifications de chaînes alkyles, modifications du cycle) ont été préparés et criblés pour leurs activités cytotoxiques, antibactérienne gram-positive et antifongique. Les résultats ont montré une absence de corrélation entre les activités cytotoxique et antibactérienne, suggérant des mécanismes de toxicité distincts. Quelques dérivés ont montré de fortes différences d’activité, notamment par une réduction de la cytotoxicité par des groupements hydroxyle ou nitrile, alors que ce dernier augmentait le potentiel antibactérien. L’activité antifongique a émergé au fil de l’élongation des chaînes alkoxydes. Ces derniers dérivés, ainsi que la dirchromone bromée ou avec un cycle aromatique supplémentaire, sont légèrement plus cytotoxiques que le composé parent. Cependant, dans l’ensemble, le pharmacophore de la dirchromone a maintenu son activité dans la majorité des cas. Ce dernier pan du projet a donc démontré la robustesse de la dirchromone vis-à-vis la substitution de son noyau de base. Cette thèse marque donc une avancée de l’accessibilité et de la compréhension des activités biologiques des dirchromones en fonction de leur structure. Elle a permis de jeter un peu de lumière sur une portion de l’espace chimique biologiquement pertinent qui auparavant demeurait inexplorée et hors d’atteinte, offrant ainsi des perspectives de recherche plus précises autour de ce squelette unique. The exploration of biologically relevant chemical space requires that some rules or sources of inspiration are used so as to achieve some degree of focus while scouting the vastness of theoretically possible carbon atoms assemblies. Among such strategies, the examination of naturally occurring substances retains a place of choice, both because this approach offers insight into structures that would have been hardly accessible through classical synthesis and because natural products are the result of constant coevolution of life forms secreting them precisely to influence other organisms. Previously, a study of the shrub Dirca palustris had led to the discovery of a family of sulfur-bearing compounds, dirchromones. These exerted cytotoxic activity and antibacterial potential against Staphylococcus aureus, and they covered a new niche of the chemical space owing to their peculiar side chain featuring a vinylsulfoxide moiety. However, their low availability from the plant material did not allow for more than mere cataloguing. In the course of this thesis, three objectives were therefore pursued: developing a synthesis of dirchromone combining accessibility, flexibility and a reasonable number of steps; determining the most relevant structural characteristics towards the biological activities; and exploring the relationship between systematic structural modifications and the cytotoxic and antibacterial activities. To begin with, a total synthesis of dirchromones was designed so as to circumvent the shortcomings of classical approaches, featuring as key steps an unusual Pummerer rearrangement allowing for an oxidation transfer, and the first reported example of a soft-enolization Baker-Venkataraman rearrangement. The whole protocol comprises seven steps which allowed to prepare dirchromone at the gram scale with an overall yield of 21 % from readily accessible reagents. The same synthesis was shown to be flexible, giving access to multiple substitutions of the core structure and also to other common chromones. At this stage, the cytotoxicity of synthetic dirchromone was confirmed on 13 malignant cell lines. Secondly, thanks to this synthetic route, various structural modifications were incorporated to the moiety that makes dirchromone unique, i.e., its sulfur-bearing side chain. This revealed in particular that the oxidation level of the sulfur was pivotal to the expression of the biological activities, with the sulfoxide being more cytotoxic whereas the sulfone was more antibacterial and the sulfide inactive in both cases. In order to grasp a broader understanding of the implication of the lateral chain on dirchromone’s reactivity, the latter was subjected to a study of its Michael acceptor behavior by reacting it with cysteamine and following the reaction by nuclear magnetic resonance. Since a surprising outcome was observed, some reaction products were characterized, highlighting a reaction sequence comprising a Michael addition, the elimination of the methylsufinyl fragment and redox conversions. The fluorescence of some of these products also highlighted that similar reactions occurred within the cytosol of cells to which dirchromone was administered. Furthermore, 32 analogs of dirchromone featuring various substituents (methylation, heteroatoms, acylation or alkoxidation with various chain lengths and branching, modification of the cyclic core) were prepared and screened for their cytotoxic, anti-Gram-positive bacteria and antifungal activities. The results showed a lack of correlation between antibacterial and cytotoxic activities, suggesting distinct toxicity mechanisms. A few derivatives induced strong difference in activity, especially by reducing cytotoxicity upon the introduction of hydroxyl or nitrile group, whereas the latter increased the antibacterial activity. An antifungal activity also arose as the alkoxide substituents’ chain length increased. The latter as well as dirchromones featuring a bromide or an additional aromatic ring were slightly more cytotoxic than the parent compound. That being said, as a whole, the pharmacophore of dirchromone maintained its activity in the majority of cases. This last part of the project therefore outlined the robustness of dirchromone towards substitution of its core structure. This thesis therefore furthered the accessibility and the understanding of the biological activities of dirchromone with regard to its structure. It hence shed a bit of light on a portion of the biologically relevant chemical space that previously remained unexplored and beyond reach, offering more precise research perspectives around this unique molecular entity

Exploring the Biologically Relevant Chemical Space for Drug Discovery

Both recent studies and our calculation suggest that the physicochemical properties of launched drugs changed continuously over the past decades. Besides shifting of commonly used properties, the average biological relevance (BR) and similarity to natural products (NPs) of launched drugs decreased, reflecting the fact that current drug discovery deviated away from NPs. To change the current situation characterized by high investment but low productivity in drug discovery, efforts should be made to improve the BR of the screening library and hunt drugs more effectively in the biologically relevant chemical space. Additionally, a multiple dimensional molecular descriptor, named the biologically relevant spectrum (BRS) was proposed for quantitative structure–activity relationships (QSAR) study or screening library preparation. Prediction models for 43 biological activity categories were developed with BRS and support vector machine (SVM). In most cases, the overall prediction accuracies were around 95% and the Matthew’s correlation coefficients (MCC) were over 0.8. Thirty-seven out of 48 drug-activity associations were successfully predicted for drugs that launched from 2006 to 2012, which were not included in the training data set. A web-server named BioRel (http://ibi.hzau.edu.cn/biorel) was developed to provide services including BR, BRS calculation, activity class, and pharmacokinetic property prediction

The anti-proliferative activity of drimia altissima and a novel isolated flavonoid glycoside against hela cervical cancer cells

Cancer is one of the leading causes of mortality worldwide. About 44% of all cancer morbidity and 53% of all cancer mortality occur in countries with a low to medium Human Development Index (HDI). Thus, cancer is rapidly emerging as a serious threat to public health in Africa and most especially, sub-Saharan Africa. The International Agency for Research on Cancer (IARC) projects that there will be 1.28 million new cancer cases and 970 000 cancer deaths in Africa by the year 2030 owing to the increase in economic development associated lifestyles. The dominant types of cancer in Africa are those related to infectious diseases such as Kaposi’s sarcoma and cervical, hepatic and urinary bladder carcinomas. The main challenge to cancer treatment in Africa is the unavailability of efficacious anticancer drugs. This is because most developing countries can only afford to procure the most basic anticancer drugs, which are also frequently unavailable due to intermittent supplies. This results in patients progressing to more advanced cancer states. One way of combating this African problem is to focus on research that aims at discovering efficacious and cost effective cancer therapies from available natural resources within the African continent. This study investigated the potential anti-proliferative activity (against HeLa cervical cancer cells) of four plants (Adansonia digitata, Ceiba pentandra, Maytenus senegalensis and Drimia altissima) commonly used in the African traditional treatment of malignancies. After in vitro bio-assay screening using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, M. senegalensis root extract (MS-R) and D. altissima bulb extract (DA-B) showed anti-proliferative activity against HeLa cervical cancer cells with IC50 values of 25 μg/mL and 1.1 μg/mL respectively. By possessing the strongest anti-proliferative activity among the tested extracts, D. altissima was selected for further studies. Liquid-liquid partitioning of the Drimia altissima bulb extract with n-hexane, ethyl acetate, and n-butanol, yielded partitions 79a – d, with the n-butanol fraction, 79d, exhibiting the strongest cytotoxic activity (IC50 = 0.497 μg/mL). Through High Content Analysis (HCA) screening, fraction 79d was found to induce marked early mitotic cell cycle arrest. Fractionation of 79d using Diaion® HP-20 open column chromatography and a stepwise gradient of reducing polarity (water-methanol-ethanol-ethyl acetate) yielded cytotoxic fractions 82b, 82c, 82d and 82e, all with significant anti-proliferative activities at the tested concentrations of 0.1, 1.0 and 10 μg/mL. Bio-assay guided fractionation of 82c (the most effective fraction at the lowest tested concentration of 0.1 μg/mL) using Sephadex® LH-20 open column chromatography and 50% MeOH led to the isolation of compound 3.17. After structural elucidation using 1D and 2D Nuclear Magnetic Resonance spectroscopy (NMR), High resolution Mass spectrometry (HRMS), Fourier-Transform Infrared spectroscopy (FT-IR), ultraviolet spectroscopy (UV) and Circular Dichroism (CD), compound 3.17 was identified as a novel C-glucosylflavonoid-O-glucoside, 6-C-[-apio-α-D-furanosyl-(1→6)-β-glucopyranosyl]-4′, 5, 7-trihydroxyflavone (Altissimin, 3.17). Compound 3.17 exhibited a dose dependant anti-proliferative activity with an IC50 of 2.44 μM. The mechanism of action for compound 3.17 was investigated through cell cycle arrest, phosphatidylserine translocation (PS), caspase activation and mitochondrial membrane depolarization. The mechanism of cell death elicited by compound 3.17 in HeLa cells was found to involve the induction of M phase cell cycle arrest with consequent activation of apoptotic cell death which was evident from annexin V staining, mitochondrial membrane potential (ΔΨm) collapse and the activation of caspases -8 and -3. In silico computational techniques were employed to virtually determine potential biological targets of compound 3.17. Target fishing using the Similarity Ensemble Approach (SEA) target prediction gave human aldose reductase (hAR, AKR1B1) the highest ranking with a p value of 2.85 x 10-24, a max Tc of 0.35 and a Z-score of 41.8217. Using AutoDock4 and the AutoDock tools suite (ADT), molecular docking of compound 3.17 in the hAR binding pocket was successfully achieved with a lower ΔG free energy binding (-9.4 kcal/mol) than that of positive control ligand 393 (-8.7 kcal/mol). In conclusion, this study identified the genus Drimia and particularly D. altissima as a potential source for novel cytotoxic compounds. The discovery of altissimin (3.17), the first flavonoid glycoside to be isolate from D. altissima, enquires into the possible existence of similar compounds within the species. In addition to the observed in vitro cytotoxic activity against HeLa cells, the potential of altissimin (3.17) as a hAR enzyme inhibitor opens up the possibility of its use as an adjunct to increase cancer cell sensitivity to chemotherapy. Thus, altissimin (3.17) shows promise as a potential anticancer agent