Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• Sumudu P. Leelananda Steffen Lindert Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210, USA 10.3762/bjoc.12.267 Abstract The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can

• data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of

• in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• 10.3762/bjoc.12.226 Abstract Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an

• encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin. Keywords: amino acid; bacterial resistance; enduracididine; natural products; peptide antibiotics; Review Introduction The enduracididines The enduracididines

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• . Succinimides are present in many biologically significant molecules and are investigated as potential pharmacophores in the research of drug discovery [11][12]. Our group has recently devised N-itaconimides for the assembly of succinimide frameworks [13][14][15][16][17][18]. As an extension of these works

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• Hui Hong Yuhui Sun Yongjun Zhou Emily Stephens Markiyan Samborskyy Peter F. Leadlay Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education

New furoisocoumarins and isocoumarins from the mangrove endophytic fungus Aspergillus sp. 085242

• Ze’en Xiao,
• Senhua Chen,
• Runlin Cai,
• Shao’e Lin,
• Kui Hong and
• Zhigang She

Beilstein J. Org. Chem. 2016, 12, 2077–2085, doi:10.3762/bjoc.12.196

• District, Shenzhen, 518102, China Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education of China, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China 10.3762/bjoc.12.196 Abstract The chemical investigation of the mangrove endophytic fungus Aspergillus

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

• Atul A. Dhavan,
• Rahul D. Kaduskar,
• Loana Musso,
• Leonardo Scaglioni,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2016, 12, 1624–1628, doi:10.3762/bjoc.12.159

• therapies and the emergence of multidrug resistant strains. Novel potent compounds endowed with new mechanisms of action are urgently needed. In this regard, natural products continue to be a rich source of biologically validated structures, which can be modified and optimized in drug discovery [1

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction

• Bo Yang,
• Chuanye Tao,
• Taofeng Shao,
• Jianxian Gong and
• Chao Che

Beilstein J. Org. Chem. 2016, 12, 1487–1492, doi:10.3762/bjoc.12.145

• diverse and biologically relevant heterocycles, and thus have been extensively investigated by organic and medicinal chemists to explore lead compounds in drug discovery efforts [7][8][9][10]. The imidazo[1,2-a]pyridine scaffold is a pharmaceutically important drug template, and its derivatives display a

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• , Australia 10.3762/bjoc.12.98 Abstract Oxindole scaffolds are prevalent in natural products and have been recognized as privileged substructures in new drug discovery. Several oxindole-containing compounds have advanced into clinical trials for the treatment of different diseases. Among these compounds

• contain two biologically important structural scaffolds, namely the 3-hydroxyoxindole and coumarin, which could be potentially used for further biological evaluation or serve as starting points in drug discovery pursuits. A highly stereoselective Mukaiyama–aldol reaction was reported by Zhou and co

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• 5,5-disubstituted hydantoins, a well-recognized scaffold for drug discovery. 2 Thiazol-4(5H)-ones 2 Thiazol-4(5H)-ones 2, which exhibit interesting applications in medicinal and pharmaceutical areas [74][75][76], can be easily synthesized and can act as (pro)nucleophiles in asymmetric catalytic

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• and 3s, which contain a fluorine atom, were obtained in good yield with good to execellent ee (Table 3, entries 6 and 14–16). Enantiomerically enriched fluorine-containing 2-oxoindoles are of great significance in drug discovery and development [45]. Unfortunately, there was no ee observed when the 3

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• , piperazine ranks among the top three N-heterocycles along with pyridine and piperidine in the U.S. FDA-approved pharmaceuticals [2]. Due to its broad utilization, piperazine has been considered as a privileged scaffold in drug discovery to combat various human diseases (Figure 1). For example, Imatinib (also

• substitutions (methyl or carboxylate). Recently, other substituents such as aryl and alkyl groups started to appear on the α-carbons of piperazine rings of various important lead compounds in the pipeline of drug discovery [7][8][9]. Vestipitant, a neurokinin-1 antagonist, is an example which is currently in

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• ]. Nowadays the major drawback of natural products research and drug discovery represents the re-isolation of known compounds and the random nature – in terms of organisms explored – by which this research is performed. Most compounds are still isolated from random sources and tested against random targets to

• find more or less useful bioactivities. More rational approaches are necessary to enhance the efficacy, efficiency, and speed of drug discovery in general and antibiotic discovery in particular. In recent years, the exploration of the chemical basis of specific and well-described bacteria–host or

• for drug discovery [24][25][26][27]. Below we provide an overview of natural products isolated from microbial symbionts of insects, and the analytical dereplication methods when these have been applied to identify the molecules. The (potential) ecological function of the identified natural products

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• metabolites is therefore of great importance to facilitate the drug discovery process [42]. For this purpose chemoselective oxidation protocols are a valuable tool since they can provide us with metabolites typically generated by cytochrome P450 enzymes. Bearing this in mind we attempted to oxygenate the

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• ; intercalation; macrocycles; multi-target drug discovery; RNA recognition; RNase mimic; Review Early childhood and overview I was born on October 8, 1957 in Evanston, Illinois, the second of three boys. Our parents, Howard E. Zimmerman and Jane Zimmerman, née Kirschenheiter, were very much in love and also

• their formation. Our own efforts to create small molecules to target the toxic RNA involved in myotonic dystrophy have expanded to include multitarget drug-discovery approaches where supramolecular design principles led to DNA and RNA-selective small molecules that function even in the complex organisms

Bright molecules for sensing, computing and imaging: a tale of two once-troubled cities

• A. Prasanna de Silva

Beilstein J. Org. Chem. 2015, 11, 2774–2784, doi:10.3762/bjoc.11.298

• -based computation can be put to use in situations which benefit from the small size of fluorescent molecules. For instance, it can be useful in drug discovery. Many of these programs employ sub-millimetric polymer beads as carriers of drug candidates. These beads have to be tagged with some

Selectively fluorinated cyclohexane building blocks: Derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane

• Mohammed Salah Ayoup,
• David B. Cordes,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 2671–2676, doi:10.3762/bjoc.11.287

• have proven invaluable in drug discovery [1] and agrochemical research programmes [2]. Most such building blocks possess aryl/heteroaryl-F, aryl/heteroaryl-(X)CF3 or variants thereof, whereas selectively fluorinated aliphatics are much rarer. We have had a focus on introducing selectively fluorinated

Smart molecules for imaging, sensing and health (SMITH)

• Bradley D. Smith

Beilstein J. Org. Chem. 2015, 11, 2540–2548, doi:10.3762/bjoc.11.274

• available for preclinical research applications including acceleration of the anticancer and obesity drug discovery, facile monitoring of bone growth, and next-generation fluorescence-guided surgery [17]. An off-shoot of this work was discovery of novel chemiluminescent squaraine rotaxane structures [39

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• therefore of great interest for drug discovery, especially for their application as anticancer agents [1]. Marine soft corals of the genus Xenia (order Alcyonacea, family Xeniidae) are known to be rich in xenicane diterpenoids. The first reported member of these metabolites was xenicin (1), isolated from

• investigations of the biological activity of these natural products, and ultimately for drug discovery. The development of short and efficient synthetic routes towards xenicane natural products therefore remains a great challenge of this exciting research field. a) Structure of xenicin (1) and b) numbering of

Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

• Jyotiprasad Mukherjee,
• Suman Sil and
• Shital Kumar Chattopadhyay

Beilstein J. Org. Chem. 2015, 11, 2487–2492, doi:10.3762/bjoc.11.270

• -225497. Keywords: cross metathesis; cyclic peptides; diversity oriented synthesis; macrocycle; Introduction Diversity-oriented synthesis (DOS) has been established as an important paradigm in drug discovery [1][2][3][4][5][6][7]. Although the major focus is on the synthesis of small molecular libraries

Synthesis of D-fructose-derived spirocyclic 2-substituted-2-oxazoline ribosides

• Madhuri Vangala and
• Ganesh P. Shinde

Beilstein J. Org. Chem. 2015, 11, 2289–2296, doi:10.3762/bjoc.11.249

• spiro [42] 2-oxazolines [43] are limited, to the best of our knowledge. With our interest in the area of glycopeptides [44] and carbohydrates [45], and owing to the importance of ribosides in general and spiroribofuranoses [46] in particular for drug discovery, in this paper, we report the synthesis of

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• toolbox [1][2][3][4][5][6]. Since its infancy in the 50’s, metathesis has grown in importance and, today, applications in a broad variety of areas such as natural product synthesis [7][8][9][10][11], polymerization [12], drug discovery [7], petrochemistry or agricultural chemistry have been reported. One

Investigation on the reactivity of α-azidochalcones with carboxylic acids: Formation of α-amido-1,3-diketones and highly substituted 2-(trifluoromethyl)oxazoles

• Kandasamy Rajaguru,
• Arumugam Mariappan,
• Rajendran Suresh,
• Periasamy Manivannan and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2015, 11, 2021–2028, doi:10.3762/bjoc.11.219

• -Azidochalcones are one of the most attractive three-atom synthons for the formation of nitrogen-containing organic motifs. Due to their versatile reactivity, they have attracted considerable attention since last decade [1][2][3][4][5][6]. In drug discovery, secondary amides are an important class of compounds

Mechanism, kinetics and selectivity of selenocyclization of 5-alkenylhydantoins: an experimental and computational study

• Biljana M. Šmit,
• Radoslav Z. Pavlović,
• Dejan A. Milenković and
• Zoran S. Marković

Beilstein J. Org. Chem. 2015, 11, 1865–1875, doi:10.3762/bjoc.11.200

• heterocyclic compounds with cyclic urea core, are widely used as intermediates in industrial production of α-amino acids [1]. They exhibit various biological activities making them attractive candidates for drug discovery [2][3][4][5][6][7][8][9][10][11]. In the most cases, the observed biological activities

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• ][21][22][23][24][25][26]. The interest of the inhibitory multivalent effect for drug discovery was demonstrated by targeting glycosidases involved in rare genetic diseases linked to misfolded proteins [24][25][26]. The first examples of multivalent iminosugars such as 2 and 3 acting as pharmacological

Three-component synthesis of C₂F₅-substituted pyrazoles from C₂F₅CH₂NH₂·HCl, NaNO₂ and electron-deficient alkynes

• Pavel K. Mykhailiuk

Beilstein J. Org. Chem. 2015, 11, 16–24, doi:10.3762/bjoc.11.3

• alkynes 1–12 with C2F5CHN2 gives 3,5-disubstituted ones. Also, alkaline hydrolysis of the ester group in 1a gave acid 25 – potential building blocks for medicinal chemistry and drug discovery: many bioactive compounds, including the insecticidal agent DP-23, contain the residue of the CF3-analogue of 25

• (Scheme 3) [54]. Finally, alkylation of pyrazole 1a with MeI afforded the product 26 in 69% yield after column chromatography. Basic hydrolysis of the ester group in 26 gave acid 27 – another potential building block for drug discovery (the corresponding CF3-acid constitutes to the known antiviral agent

• ). Therefore, given the importance of fluorinated pyrazoles, it is desirable that scientists will soon use this extremely useful practical reaction in synthetic organic chemistry, drug discovery and agrochemistry (where the need for robust reactions is high). Experimental General procedure: To a stirred