SynRoute: A Retrosynthetic Planning Software.

Computer-assisted synthetic planning has seen major advancements that stem from the availability of large reaction databases and artificial intelligence methodologies. SynRoute is a new retrosynthetic planning software tool that uses a relatively small number of general reaction templates, currently 263, along with a literature-based reaction database to find short, practical synthetic routes for target compounds. For each reaction template, a machine learning classifier is trained using data from the Pistachio reaction database to predict whether new computer-generated reactions based on the template are likely to work experimentally in the laboratory. This reaction generation methodology is used together with a vectorized Dijkstra-like search of top-scoring routes organized by synthetic strategies for easy browsing by a synthetic chemist. SynRoute was able to find routes for an average of 83% of compounds based on selection of random subsets of drug-like compounds from the ChEMBL database. Laboratory evaluation of 12 routes produced by SynRoute, to synthesize compounds not from the previous random subsets, demonstrated the ability to produce feasible overall synthetic strategies for all compounds evaluated.

Machine Learning Models for Predicting Molecular UV-Vis Spectra with Quantum Mechanical Properties.

Accurate understanding of ultraviolet-visible (UV-vis) spectra is critical for the high-throughput synthesis of compounds for drug discovery. Experimentally determining UV-vis spectra can become expensive when dealing with a large quantity of novel compounds. This provides us an opportunity to drive computational advances in molecular property predictions using quantum mechanics and machine learning methods. In this work, we use both quantum mechanically (QM) predicted and experimentally measured UV-vis spectra as input to devise four different machine learning architectures, UVvis-SchNet, UVvis-DTNN, UVvis-Transformer, and UVvis-MPNN, and assess the performance of each method. We find that the UVvis-MPNN model outperforms the other models when using optimized 3D coordinates and QM predicted spectra as input features. This model has the highest performance for predicting UV-vis spectra with a training RMSE of 0.06 and validation RMSE of 0.08. Most importantly, our model can be used for the challenging task of predicting differences in the UV-vis spectral signatures of regioisomers.

UV-adVISor: Attention-Based Recurrent Neural Networks to Predict UV-Vis Spectra.

Ultraviolet-visible (UV-Vis) absorption spectra are routinely collected as part of high-performance liquid chromatography (HPLC) analysis systems and can be used to identify chemical reaction products by comparison to the reference spectra. Here, we present UV-adVISor as a new computational tool for predicting the UV-Vis spectra from a molecule's structure alone. UV-Vis prediction was approached as a sequence-to-sequence problem. We utilized Long-Short Term Memory and attention-based neural networks with Extended Connectivity Fingerprint Diameter 6 or molecule SMILES to generate predictive models for the UV spectra. We have produced two spectrum datasets (dataset I, N = 949, and dataset II, N = 2222) using different compound collections and spectrum acquisition methods to train, validate, and test our models. We evaluated the prediction accuracy of the complete spectra by the correspondence of wavelengths of absorbance maxima and with a series of statistical measures (the best test set median model parameters are in parentheses for model II), including RMSE (0.064), R2 (0.71), and dynamic time warping (DTW, 0.194) of the entire spectrum curve. Scrambling molecule structures with the experimental spectra during training resulted in a degraded R2, confirming the utility of the approaches for prediction. UV-adVISor is able to provide fast and accurate predictions for libraries of compounds.

Carbon-14 labeling of K777•HCl, a therapeutic agent for Chagas disease.

The antitrypanosomal agent K777•HCl was labeled with carbon-14 to support absorption, distribution, metabolism, and excretion studies of this potential new drug for the treatment of Chagas disease. The radiolabeled compound was prepared in eight steps from [(14) C(U)]-(l)-phenylalanine with a specific activity of 54.4 mCi/mmol and an overall radiochemical yield of 4.1%.

Accurate atom-mapping computation for biochemical reactions.

The complete atom mapping of a chemical reaction is a bijection of the reactant atoms to the product atoms that specifies the terminus of each reactant atom. Atom mapping of biochemical reactions is useful for many applications of systems biology, in particular for metabolic engineering where synthesizing new biochemical pathways has to take into account for the number of carbon atoms from a source compound that are conserved in the synthesis of a target compound. Rapid, accurate computation of the atom mapping(s) of a biochemical reaction remains elusive despite significant work on this topic. In particular, past researchers did not validate the accuracy of mapping algorithms. We introduce a new method for computing atom mappings called the minimum weighted edit-distance (MWED) metric. The metric is based on bond propensity to react and computes biochemically valid atom mappings for a large percentage of biochemical reactions. MWED models can be formulated efficiently as Mixed-Integer Linear Programs (MILPs). We have demonstrated this approach on 7501 reactions of the MetaCyc database for which 87% of the models could be solved in less than 10 s. For 2.1% of the reactions, we found multiple optimal atom mappings. We show that the error rate is 0.9% (22 reactions) by comparing these atom mappings to 2446 atom mappings of the manually curated Kyoto Encyclopedia of Genes and Genomes (KEGG) RPAIR database. To our knowledge, our computational atom-mapping approach is the most accurate and among the fastest published to date. The atom-mapping data will be available in the MetaCyc database later in 2012; the atom-mapping software will be available within the Pathway Tools software later in 2012.

Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis.

OBJECTIVES: New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance to existing agents and shorten the duration of therapy. Targeting DNA gyrase is a clinically validated therapeutic approach using fluoroquinolone antibiotics to target the gyrase subunit A (GyrA) of the heterotetramer. Increasing resistance to fluoroquinolones has driven interest in targeting the gyrase subunit B (GyrB), which has not been targeted for TB. The biological activities of two potent small-molecule inhibitors of GyrB have been characterized to validate its targeting as a therapeutic strategy for treating TB. MATERIALS AND METHODS: Novobiocin and aminobenzimidazole 1 (AB-1) were tested for their activity against Mycobacterium tuberculosis (Mtb) H37Rv and other mycobacteria. AB-1 and novobiocin were also evaluated for their interaction with rifampicin and isoniazid as well as their potential for cytotoxicity. Finally, AB-1 was tested for in vivo efficacy in a murine model of TB. RESULTS: Novobiocin and AB-1 have both been shown to be active against Mtb with MIC values of 4 and 1 mg/L, respectively. Only AB-1 exhibited time-dependent bactericidal activity against drug-susceptible and drug-resistant mycobacteria, including a fluoroquinolone-resistant strain. AB-1 had potent activity in the low oxygen recovery assay model for non-replicating persistent Mtb. Additionally, AB-1 has no interaction with isoniazid and rifampicin, and has no cross-resistance with fluoroquinolones. In a murine model of TB, AB-1 significantly reduced lung cfu counts in a dose-dependent manner. CONCLUSIONS: Aminobenzimidazole inhibitors of GyrB exhibit many of the characteristics required for their consideration as a potential front-line antimycobacterial therapeutic.

A high-throughput fluorescence polarization assay for inhibitors of gyrase B.

DNA gyrase, a type II topoisomerase that introduces negative supercoils into DNA, is a validated antibacterial drug target. The holoenzyme is composed of 2 subunits, gyrase A (GyrA) and gyrase B (GyrB), which form a functional A(2)B(2) heterotetramer required for bacterial viability. A novel fluorescence polarization (FP) assay has been developed and optimized to detect inhibitors that bind to the adenosine triphosphate (ATP) binding domain of GyrB. Guided by the crystal structure of the natural product novobiocin bound to GyrB, a novel novobiocin-Texas Red probe (Novo-TRX) was designed and synthesized for use in a high-throughput FP assay. The binding kinetics of the interaction of Novo-TRX with GyrB from Francisella tularensis has been characterized, as well as the effect of common buffer additives on the interaction. The assay was developed into a 21-µL, 384-well assay format and has been validated for use in high-throughput screening against a collection of Food and Drug Administration-approved compounds. The assay performed with an average Z' factor of 0.80 and was able to identify GyrB inhibitors from a screening library.

Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.

Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.

Enantioselective alpha-amination of 1,3-dicarbonyl compounds using squaramide derivatives as hydrogen bonding catalysts.

Catalytic enantioselective alpha-hydrazination of 1,3-dicarbonyl compounds with azodicarboxylates was investigated in the presence of our newly developed hydrogen bonding catalyst, squaramide 3j. High yields and high enantioselectivities were achieved with low catalyst loading under mild conditions.

Chiral squaramide derivatives are excellent hydrogen bond donor catalysts.

Thioureas represent the dominant platform for hydrogen bond promoted asymmetric catalysts. A large number of reactions, reported in scores of publications, have been successfully promoted by chiral thioureas. The present paper reports the use of squaramides as a highly effective new scaffold for the development of chiral hydrogen bond donor catalysts. Squaramide catalysts are very simple to prepare. The (-)-cinchonine modified squaramide (5), easily prepared through a two-step process from methyl squarate, was shown to be an effective catalyst, even at catalyst loadings as low as 0.1 mol%, for the conjugate addition reactions of 1,3-dicarbonyl compounds to beta-nitrostyrenes. The addition products were obtained in high yields and excellent enantioselectivities.

Palladium-catalyzed beta-allylation of 2,3-disubstituted indoles.

Given the prevalence of the indole nucleus in biologically active compounds, the direct C3-functionalization of 2,3-disubstituted indoles represents an important problem. Described is a general, high-yielding method for the palladium-catalyzed beta-allylation of carba- and heterocycle fused indoles, including complex natural product substrates.

Biomimetic synthesis of antimalarial naphthoquinones.

The total synthesis of naphthoquinone natural products isolated from the Bignoniaceae plant family is described. Pinnatal, isopinnatal, sterekunthals A and B, pyranokunthones A and B, and anthrakunthone have been prepared along the lines of a biosynthetic proposal involving pericyclic reactions as key steps. The first case of catalysis in oxa 6pi electrocyclizations is reported.

Biomimetic synthesis of (+/-)-pinnatal and (+/-)-sterekunthal A.

Concise biomimetic syntheses of the antimalarial naphthoquinones (+/-)-pinnatal and (+/-)-sterekunthal A are described.

Unusually low barrier to carbamate C-N rotation.

The barrier for rotation about an N-alkylcarbamate C(carbonyl)-N bond is around 16 kcal/mol. In the case of an N-phenylcarbamate, the rotational barrier is lowered to 12.5 kcal/mol, but with N-(2-pyrimidyl)carbamates the barriers are so low (<9 kcal/mol) that the syn and anti rotamers cannot be observed as separate signals by 500 MHz NMR spectroscopy at 183 K. X-ray and computational data show that the N-(2-pyrimidyl) carbamates have C(carbonyl)-N bonds that are on average 0.03 A longer than for related N-phenylcarbamates. The computational results trace the origin of the effect to increased single bond character for the C(carbonyl)-N bond due to the increased electron-withdrawing ability of the pyrimidyl ring.