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Concept: Medicinal chemistry

1524

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

Concepts: Pharmacology, Clinical trial, Drug discovery, Medicinal chemistry, Natural product, High-throughput screening, Natural products

186

Medicinal chemists' “intuition” is critical for success in modern drug discovery. Early in the discovery process, chemists select a subset of compounds for further research, often from many viable candidates. These decisions determine the success of a discovery campaign, and ultimately what kind of drugs are developed and marketed to the public. Surprisingly little is known about the cognitive aspects of chemists' decision-making when they prioritize compounds. We investigate 1) how and to what extent chemists simplify the problem of identifying promising compounds, 2) whether chemists agree with each other about the criteria used for such decisions, and 3) how accurately chemists report the criteria they use for these decisions. Chemists were surveyed and asked to select chemical fragments that they would be willing to develop into a lead compound from a set of ∼4,000 available fragments. Based on each chemist’s selections, computational classifiers were built to model each chemist’s selection strategy. Results suggest that chemists greatly simplified the problem, typically using only 1-2 of many possible parameters when making their selections. Although chemists tended to use the same parameters to select compounds, differing value preferences for these parameters led to an overall lack of consensus in compound selections. Moreover, what little agreement there was among the chemists was largely in what fragments were undesirable. Furthermore, chemists were often unaware of the parameters (such as compound size) which were statistically significant in their selections, and overestimated the number of parameters they employed. A critical evaluation of the problem space faced by medicinal chemists and cognitive models of categorization were especially useful in understanding the low consensus between chemists.

Concepts: Pharmacology, Critical thinking, Chemistry, Cognition, Drug discovery, Drug design, Medicinal chemistry, Selection

168

We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.

Concepts: Pharmacology, Sol-gel, Drugs, Membrane biology, Medicinal chemistry, Pharmacokinetics, Biopharmaceutics Classification System, Digestion

161

Traditional drug discovery approaches are mainly relied on the observed phenotypic changes following administration of a plant extract, drug candidate or natural product. Recently, target-based approaches are becoming more popular. The present study aimed to identify the cellular targets of crocin, the bioactive dietary carotenoid present in saffron, using an affinity-based method.

Concepts: Drug discovery, Medicinal chemistry, Natural product, Crocin, Crocetin

150

Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly’s Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds.

Concepts: Cancer, Signal transduction, Angiogenesis, Drug discovery, Medicinal chemistry, Natural products

145

Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused by the interplay between drug pharmacology and the patients' (patho)physiological status. Individual variations in (patho)physiological status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, and disease related factors. Identification and quantification of predictors of inter-individual variability in drug pharmacology is necessary to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top of the conventional covariates in predicting drug PK. Additionally, employing pharmacometabolomics to predict drug PD is highlighted, and we suggest not only considering the endogenous metabolites as static variables but to include also drug dose and temporal changes in drug concentration in these studies. Although there are many endogenous metabolite biomarkers identified to predict PK and more often to predict PD, validation of these biomarkers in terms of specificity, sensitivity, reproducibility and clinical relevance is highly important. Furthermore, the application of these identified biomarkers in routine clinical practice deserves notable attention to truly personalize drug treatment in the near future.

Concepts: Scientific method, Pharmacology, Medicine, Prediction, Medicinal chemistry, Pharmacokinetics, Pharmacy, Pharmacodynamics

143

Two new 16-nor limonoids, harperspinoids A and B (1 and 2), with a unique 7/5/5/6/5 ring system, have been isolated from the plant Harrisonia perforate together with a known one, Harperforin G (3). Their structures were elucidated by NMR spectroscopy, X-ray diffraction analysis and computational modelling. Compound 1 exists as polymorphic crystals. Conformations of 1 in solution were further discussed based on the computational results. These compounds exhibited notable inhibitory activity against the 11β-HSD1 enzyme. Compound 3 had potencies for the inhibition of human 11β-HSD1 with high selectivity against 11β-HSD2 (IC50 0.58 μM, SI > 174). Molecular docking and quantitative structure-activity relationship studies revealed a mixed regulatory mechanism.

Concepts: Protein structure, Diffraction, X-ray, Crystallography, Chemistry, Enzyme inhibitor, Medicinal chemistry, Protein nuclear magnetic resonance spectroscopy

33

Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels.

Concepts: Pharmacology, Antibiotic, Medicinal chemistry, Topical, Route of administration, Pharmacokinetics, Biopharmaceutics Classification System, Bioavailability

29

Halogen bonding has been known in material science for decades, but until recently, halogen bonds in protein-ligand interactions were largely the result of serendipitous discovery rather than rational design. In this perspective, we provide insights into the phenomenon of halogen bonding, with special focus on its role in drug discovery. We summarize the theoretical background defining its strength and directionality, provide a systematic analysis of its occurrence and interaction geometries in protein-ligand complexes, and give recent examples where halogen bonding has been successfully harnessed for lead identification and optimization. In the light of these data, we discuss the potential and limitations of exploiting halogen bonds for molecular recognition and rational drug design.

Concepts: Pharmacology, Molecule, Chemistry, Drug discovery, Drug design, Materials science, Medicinal chemistry, Molecular Conceptor

28

In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co-crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping-check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant-driven cancer cell line, Karpas299. And six of them showed a good anti-viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508-5181 (from Specs), which gave a half maximal inhibitory concentration (IC(50) ) of 5.3 μm.

Concepts: Cancer, Computational chemistry, Enzyme inhibitor, Virtual screening, Chemical compound, Medicinal chemistry, Anaplastic large cell lymphoma, Pharmacophore