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

• methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. Keywords: ADME; computer-aided drug design; docking; free energy; high-throughput screening; LBDD; lead optimization

• ; machine learning; pharmacophore; QSAR; SBDD; scoring; target flexibility; Introduction Bringing a pharmaceutical drug to the market is a long term process that costs billions of dollars. In 2014, the Tufts Center for the Study of Drug Development estimated that the cost associated with developing and

Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides

• Lena Huck,
• Juan F. González,
• Elena de la Cuesta and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2016, 12, 1772–1777, doi:10.3762/bjoc.12.166

• providing a fast and efficient access to an important pharmacophore in the design of enzyme inhibitors. Furthermore, the aziridines could also be transformed into α,β-diketoamides, which were suitable precursors for nitrogen heterocycles bearing a peptide side chain. NOE effects in compound 2f. Summary of

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• serious Gram-positive infections, linezolid, was introduced in the markets in the year 2000. While also binding to the 50S subunit, it seems to unfold its inhibiting activity in a unique and early stage [13][14]. The nomenclature of the linezolid structure is shown in Figure 1 along with the pharmacophore

• were collected within a 40 kJ/mol window (Figure 6). The following points can be concluded from our computations: 1) The pharmacophore portion of linezolid is structurally preserved. 2) The H-bond between the linezolid side chain and G2540 phosphate group (Haloarcula marismortui numbering used

• , the remaining pharmacophore part fits perfectly into the binding site. What makes the difference in the relative binding energies between those two compounds seems to be the steric repulsion exerted by the methyl group of 6. This repulsion causes a twisting of the G2540 nucleobase and hence the

Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

• Hang Ren,
• Haoyun An,
• Paul J. Hatala,
• William C. Stevens Jr,
• Jingchao Tao and
• Baicheng He

Beilstein J. Org. Chem. 2015, 11, 2509–2520, doi:10.3762/bjoc.11.272

• -D-riboside (6-β-D-MPR) is an isolated antibiotic agent that possesses potent antifungal, antiviral, and antitumor activities [44]. In order to explore the effect of fluorine on the biological activity of this pharmacophore, we synthesized 6-methylpurine-3’-deoxy-3’-fluoro-β-D-riboside (4) (Scheme 2

• -chlorinated compound 49, which was deprotected under ammonia treatment to complete the desired final product 21. In order to further explore the SAR of this pharmacophore, we constructed 3’-deoxy-3’-fluoroguanosine (23, Scheme 5). N2-Acetyl-6-O-(diphenylcarbamoyl)guanine (50) was prepared according to

Synthesis, antimicrobial and cytotoxicity evaluation of new cholesterol congeners

• Mohamed Ramadan El Sayed Aly,
• Hosam Ali Saad and
• Shams Hashim Abdel-Hafez

Beilstein J. Org. Chem. 2015, 11, 1922–1932, doi:10.3762/bjoc.11.208

• pharmacophoric conjugates through CuAAC. Basically, these conjugates included cholesterol and 1,2,3-triazole moieties, while the third, the pharmacophore, was either a chalcone, a lipophilic residue or a carbohydrate tag. These compounds were successfully prepared in good yields and characterized by NMR, MS and

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• [2,3,4-kl]acridin-4-one scaffold which could be considered as the pharmacophore. The cytotoxicity of 69–76 changes depending on the substituents attached to the benzoquinone moiety (Figure 10). Furthermore, shermilamines C (28), D (77) and F (30) also represent one of the interesting anticancer alkaloids

• . Its structural motif, 7H-pyrido[2,3,4-kl]acridine fusing with a 2H-1,4-thiazin-3(4H)-one ring (Figure 11) seems to be less potent than that of 62 [46][79][80]. Ascididemin (42) demonstrated interesting antiproliferative activitiy and its pharmacophore 9H-quinolino[4,3,2-de][1,10]phenanthrolin-9-one

• with 60 is more cytotoxic than the reduced alkylated form found in kuanoniamines (B–D) (86–88) [85][86]. Although all the pyridoacridines have not been tested on the same cancer cell lines, 9H-quinolino[4,3,2-de][1,10]phenanthrolin-9-one represents the most cytotoxic pharmacophore with a large

3-Glucosylated 5-amino-1,2,4-oxadiazoles: synthesis and evaluation as glycogen phosphorylase inhibitors

• Marion Donnier-Maréchal,
• David Goyard,
• Vincent Folliard,
• Tibor Docsa,
• Pal Gergely,
• Jean-Pierre Praly and
• Sébastien Vidal

Beilstein J. Org. Chem. 2015, 11, 499–503, doi:10.3762/bjoc.11.56

• as aryl moieties, with 2-naphthyl identified as the best pharmacophore for the series discussed above (Figure 1, D–I). Nevertheless, hydrogen bonds might also be created in this secondary binding site with other residues. The introduction of hydrogen bond donors and/or acceptors at the 5-position of

• very recently reported in the context of heterocyclic chemistry [29] and we have applied it with success to our GP inhibitor design. The dimethylamino group (Scheme 1, a) was chosen as a small pharmacophore that can be readily accommodated in the GP’s catalytic site. Aromatic moieties were also

• selected (Scheme 1, b and c) for their expected hydrophobic contact with the enzyme. The tetrahydroisoquinoline moiety (Scheme 1, c) was particularly interesting due to its structural analogy with the 2-naphthyl residue, which is identified as the best pharmacophore in the GP inhibitor series. The

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• -imidazo[1,2-b]pyrazole; isocyanide; multicomponent reaction; N-heterocycles; Introduction For the relatively rapid design and construction of a diverse, large pharmacophore library, the basic concepts of diversity-oriented synthesis and isocyanide-based multicomponent reactions, such as the Ugi four

Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines

• Jian-bo Xie,
• Jian Luo,
• Timothy R. Winn,
• David B. Cordes and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 746–751, doi:10.3762/bjoc.10.69

• reported so far [14][15][16][17][18][19][20]. Among the resulting products from the above methods, (R)-(1-amino-3-methylbutyl)boronic acid served as the key mechanism-based pharmacophore in the anticancer drug Velcade, which was the first FDA approved proteasome inhibitor, and has been in clinical use for

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• sterically hindred 64 (Scheme 20) [61] in a similar MAO-N/MCR combination. In this way, dipeptide mimics 66 were obtained in good yields (75–83%), however, now with very high diastereomeric (>98%) and enantiomeric excesses (>99%). γ-lactams The γ-lactam unit is an important dipeptide pharmacophore since it

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• pharmacophore of the maytansinoids. All other derivatives show strong to moderate antiproliferative activity, irrespective whether the lack of the N-methyl group, and or the oxirane groups or not. This is in line with the view obtained from structure–activity relationship studies that these tailoring

A catalyst-free multicomponent domino sequence for the diastereoselective synthesis of (E)-3-[2-arylcarbonyl-3-(arylamino)allyl]chromen-4-ones

• Pitchaimani Prasanna,
• Pethaiah Gunasekaran,
• Subbu Perumal and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2014, 10, 459–465, doi:10.3762/bjoc.10.43

• [21]. In view of its importance chromone has emerged as a pharmacophore in drug discovery programmes, leading to several drugs in the market (e.g. cromolyn and nedocromil) and thereby continuing to draw the attention of synthetic organic and medicinal chemists [22][23][24]. However, there are

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• is the key pharmacophore of these drugs. A series of semi-synthetic derivatives of artemisinin were synthesized: artesunate, artemether, and artemisone (Figure 2). Currently, drugs based on these compounds are considered as the most efficacious for the treatment of malaria [52][53][54][55][56][57][58

• pharmacophore was synthesized in two steps by the oxidation of alcohol 156 with H5IO6/RuCl3 followed by amidation of the acid 157 (Scheme 39) [88]. It was shown that compound 158 exhibits antimalarial activity comparable with that of artemisinin [88]. Plakinic acids belong to a large family of natural products

IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives

• Caifei Tang,
• Zhiming Li and
• Quanrui Wang

Beilstein J. Org. Chem. 2013, 9, 2629–2634, doi:10.3762/bjoc.9.298

• pyrimidine moiety is an important pharmacophore [1]. Especially, the fused bi- or tricyclic heterocyles containing a pyrimidine motif have received considerable interest in the design and discovery of new compounds for pharmaceutical and herbicidal applications [2][3]. For example, the pyrrolo[2,3-d

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• part of the pharmacophore rather than simply imparting a modicum of increased solubility or tuning a parameter such as LogP [22]. An important example of de novo synthesis of the pyridine core can be found in the syntheses of nicotinic acid (1.12, vitamin B3/niacin) and nicotinamide (1.18, constituent

• structures of pioglitazone and rosiglitazone show common structural features bearing a distal pyridine ring linked to the thiazolidinedione pharmacophore. In rosiglitazone the pyridine unit is introduced via an SNAr reaction between N-methylethanolamine (1.44) and 2-chloropyridine (1.43) which in turn is

• affinity is nowadays a vital part of assessing preclinical risks of new drug candidates [73]. The piperidine unit is also incorporated into drugs in order to fulfil more significant tasks, i.e. being part of the pharmacophore itself or providing extended H-bonding networks for improved binding affinities

Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives

• Aleksandra Jankowiak,
• Emilia Obijalska and
• Piotr Kaszynski

Beilstein J. Org. Chem. 2013, 9, 1873–1880, doi:10.3762/bjoc.9.219

• cyclization of fluorides II (Figure 1) in the presence of Ca2+ ions [7]. A further progress in the investigation of cation 1a and its applications as a pharmacophore or a component of organic materials requires access to functionalized derivatives, in which substituents control the properties and allow the

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• skeleton is frequently used as a pharmacophore for the modification of known pharmaceuticals. Triazole analogues of several bioactive compounds have recently been reported. Examples are those of the well-known highly functionalized antiviral cyclic amino acid derivatives oseltamivir and zanamivir (5 and 6

Zanthoxoaporphines A–C: Three new larvicidal dibenzo[de,g]quinolin-7-one alkaloids from Zanthoxylum paracanthum (Rutaceae)

• Fidelis N. Samita,
• Louis P. Sandjo,
• Isaiah O. Ndiege,
• Ahmed Hassanali and
• Wilber Lwande

Beilstein J. Org. Chem. 2013, 9, 447–452, doi:10.3762/bjoc.9.47

• from the same family, and the mode of action of these alkaloids could be the same. Zanthoxoaporphine A (2) and liriodenine, which are oxoaporphines, are more active than dicentrine (aporphine). The isoquinoline moiety could be the pharmacophore of this class of compounds and the presence of a ketone at

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• able to modulate dopamine receptors because of their ability to place the carboxamide NH2 pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation

• a type II β-turn. It was speculated that the prolyl derivatives with the C-terminal L-prolyl residue are capable of adopting a conformation that places key pharmacophore moieties in the same relative topological space that these moieties occupy in the peptidomimetics constrained to a type II β-turn

• postulated that these highly constrained molecules are able to produce a modulatory response because each can present the necessary topological arrangement of key pharmacophore moieties in a manner similar to that of PLG peptidomimetics that are restricted to a type II β-turn conformation. A comparison of

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• of pharmacophore-based combinatorial libraries [26] and identification of new peptidomimetic scaffolds of potential interest in drug discovery [27][28][29][30], we evaluated the THBC-DKP-based scaffold as a potential suitable motif for the creation of unusual reverse-turn nucleators. Reverse turns

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• heterocyclic N-thioethylamide-based HDAC inhibitors based on the psammaplin A pharmacophore and rationalised the results using computational modelling [22]. While prereduced psammaplin A and thiol-containing analogues displayed nanomolar to subnanomolar potencies in vitro, they only displayed modest potencies

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• covered here, there appears to be little rationale for targeting both cruzain and TcCYP51. On the other hand, the surprising potency of analogue 8 does suggest this as a new lead scaffold for the development of novel TcCYP51 inhibitors. We next sought to define the minimal pharmacophore within 8 required

• effect at the highest concentration examined (10 μM). Thus, compound 13 can be considered to represent a “minimal pharmacophore” that retains reasonable affinity for TcCYP51 in vitro while also conferring an effect on T. cruzi parasites in culture. Future work will focus on further refining the in vitro

Engineering of indole-based tethered biheterocyclic alkaloid meridianin into β-carboline-derived tetracyclic polyheterocycles via amino functionalization/6-endo cationic π-cyclization

• Piyush K. Agarwal,
• Meena D. Dathi,
• Mohammad Saifuddin and
• Bijoy Kundu

Beilstein J. Org. Chem. 2012, 8, 1901–1908, doi:10.3762/bjoc.8.220

• ring to facilitate cationic π-cyclization. Keywords: cyclization; indole; meridianin; natural products; nitrogen heterocycles; Introduction Indole is an important pharmacophore present in many natural and designed polyheterocyclic synthetic products of therapeutic importance [1][2][3]. The range of

Exploring chemical diversity via a modular reaction pairing strategy

• Joanna K. Loh,
• Sun Young Yoon,
• Thiwanka B. Samarakoon,
• Alan Rolfe,
• Patrick Porubsky,
• Benjamin Neuenswander,
• Gerald H. Lushington and
• Paul R. Hanson

Beilstein J. Org. Chem. 2012, 8, 1293–1302, doi:10.3762/bjoc.8.147

• different substituents. This greater sensitivity on the part of the highlighted library should correspond to greater conformational diversity, which implies sampling of a broader range of property and pharmacophore space than those libraries with lesser conformational diversity. Quantitative estimate of

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

• Hiroki Oguri,
• Haruki Mizoguchi,
• Hideaki Oikawa,
• Aki Ishiyama,
• Masato Iwatsuki,
• Kazuhiko Otoguro and
• Satoshi Ōmura

Beilstein J. Org. Chem. 2012, 8, 930–940, doi:10.3762/bjoc.8.105

• pharmacophore, based on the key features of scaffold, substructure and stereochemistry, which could be the proof of concept of our synthetic approach toward lead generation exploiting natural-product-inspired collections. (a) Biosynthetic outline of aromatic polyketides; (b) structure of indole alkaloids