A distance function for retrieval of active molecules from complex chemical space representations

The concept of chemical space is of fundamental importance for chemoinformatics research. It is generally thought that high-dimensional space representations are too complex for the successful application of many compound classification or virtual screening methods. Here, we show that a simple "activity-centered" distance function is capable of accurately detecting molecular similarity relationships in "raw" chemical spaces of high dimensionality.     

A Consensus Compound/Bioactivity Dataset for Data-Driven Drug Design and Chemogenomics

Publicly available compound and bioactivity databases provide an essential basis for data-driven applications in life-science research and drug design. By analyzing several bioactivity repositories, we discovered differences in compound and target coverage advocating the combined use of data from multiple sources. Using data from ChEMBL, PubChem, IUPHAR/BPS, BindingDB, and Probes & Drugs, we assembled a consensus dataset focusing on small molecules with bioactivity on human macromolecular targets. This allowed an improved coverage of compound space and targets, and an automated comparison and curation of structural and bioactivity data to reveal potentially erroneous entries and increase confidence. The consensus dataset comprised of more than 1.1 million compounds with over 10.9 million bioactivity data points with annotations on assay type and bioactivity confidence, providing a useful ensemble for computational applications in drug design and chemogenomics.     

Synthesis of Ajoene Analogues by Novel Synthetic Strategies

Ajoene is a compound found in garlic extracts exhibiting a large range of biological activity. Novel ajoene analogues have been prepared in the search of compounds with superior bioactivity. Modifications include the alteration of the sulfoxide, the central alkene and the terminal allyl groups.     

Xenobiotic biotransformation of 4-methoxy-N-methyl-2-quinolone, isolated from Zanthoxylum monophyllum

Phytochemical evaluation of Zanthoxylum monophyllum has led to the isolation of the alkaloid 4-methoxy-N-methyl-2-quinolone (1) with a significant activity against methicillin-resistant Staphylococcus aureus (MRSA), with an IC50 value of 1.5 microg/mL. Xenobiotic biotransformation of 1 has been conducted with the general goal of increasing the bioactivity of the compound and contributing new leads for further pharmacological research. Twenty-nine microorganisms were used for screening and two (Aspergillus flavus and Cunninghamella echinulata var. echinulata) were able to transform compound 1 to 4-methoxy-2-quinolone (2). Structural identification of the compounds was based on NMR, IR, and MS data.     

Design,synthesis, and insecticidal bioactivities evaluation of pyrrole- and dihydropyrrole-fused neonicotinoid analogs containing chlorothiazole ring

Chlorothiazole ring, as a substituted heterocycle, frequently occurred in structures of various insecticides, and brought positive effect on bioactivity. In purpose to find novel neonicotinoids, a series of pyrrole- and dihydropyrrole-fused neonicotinoid analogs containing chlorothiazole ring were synthesized for the first time. Results of the following biological assays showed that compounds 5a-c achieved good insecticidal activity against Aphis craccivora, and compound 5h exhibited good activity against Nilaparvata lugens.     

Chemical markers’ fishing and knockout for holistic activity and interaction evaluation of the components in herbal medicines

A strategy based on chemical markers’ fishing and knockout has been proposed for holistic activity and interaction evaluation of the bioactive components in herbal medicines (HMs). It was devised to screen bioactive-compound group that represents the efficacy of HM, estimate the bioactivity contribution of each component and elucidate the interactions of multi-components. This strategy was accomplished through the following steps: (1) screen out the chemical markers (target peaks) in a HM fingerprint using online two-dimensional turbulent flow chromatography/liquid chromatography–mass spectrometry technique, (2) fish target peaks and knockout any interested peak, and (3) evaluate the bioactivities of fishing and knockout portions. After comparison of the bioactivities of samples containing different target peaks, the efficacy of target-peak group, bioactivity contribution of each compound, and the interactions of multi-components are elucidated. Using Acetylcholinesterase (AChE) and Bulbs of Lycoris radiata (L. Herit.) Herb. (BLR) as the experimental materials, four target peaks were screened out as the AChE binders. By target peaks’ fishing and knockout, combined with activity evaluation, we observed that the bioactivity of the four-peak mixture is similar with the global bioactivity of BLR extract, and there are significant suppressive actions among these four target peaks. These results indicate that this proposed strategy is a useful approach for holistic screening of bioactive-compound group and elucidation of the multi-component interactions in HM.     

Improved electron-conformational method of pharmacophore identification and bioactivity prediction. Application to angiotensin converting enzyme inhibitors

The electron-conformational (EC) method of pharmacophore (Pha) identification and bioactivity prediction, suggested earlier, is given here two major improvements. First, an atomic index of orbital and charge controlled interaction is introduced to better represent the ligand (substrate) in its interaction with the bioreceptor. Second, the multiconformational problem is considered in view of ligand-receptor binding states, resulting in essential simplification of the expression of bioactivity. The details of the improved EC method are demonstrated in application to the problem of angiotensin converting enzyme (ACE) inhibitors. The Pha of the latter is identified by separation of the heavily populated conformations of the chosen 51 compounds (the training set), calculation of the electronic structure, construction of their EC matrixes of congruity, and processing of the latter in comparison with the activities to reveal a common submatrix of all the active only compounds that describes the Pha. The latter contains three oxygen atoms plus a fourth atom X = S, N, O at certain interatomic distances and with restricted electronic parameters (within assumed tolerances), the position of the atom X being more changeable from one active compound to another. For quantitative prediction of the bioactivity, an expression is deduced which takes into account the duly parametrized influence of auxiliary groups (AG) which, being positioned outside the Pha, either diminish the activity (antipharmacophore shielding) or enhance it. It is shown that in case of many conformations of the same compound only one of them, that of the lowest energy which has the Pha, should be parametrized. The 15 parameters chosen to represent the AG in case of ACE inhibitors are weighted by variational (adjustable) coefficients which are determined from a regression treatment of the calculated versus known activities in the training set. Then the formulas with known coefficients are used to validate the method by calculating the bioactivity of other compounds not used in the training set. The prediction of the activity proved to be more than 90% (within experimental error and available compounds) qualitatively (yes, no) and about 60%-70% quantitatively.     

Biocatalyzed cross-coupling of sinomenine and 1, 2-dihydroxybenzene by Coriolus unicolor

Sinomenine is a clinically available drug for the treatment of rheumatoid arthritis(RA).In a continuous research aiming at discovery of sinomenine derivates with better bioactivity,a cross-coupling reaction of sinomenine and 1,2-dihydroxybenzene catalyzed by a fungus Coriolus unicolor afforded an unique C-C cross-coupled compound 2,together with(S)-disinomenine and (R)-disinomenine.The structure of 2 was elucidated by MS and NMR spectroscopy.Compound 2 was further assayed for the inhibitory activity on IL-6 overproduction in SW982 cells and exhibited a much more potent activity on IL-6(96%inhibition) compared with those of(S)-disinomenine and sinomenine(17%and 12%inhibition,respectively).     

New 3,4-Annelated Coumarin Derivatives: Synthesis, Antimicrobial Activity, Antioxidant Capacity, and Molecular Modeling

The one pot reaction preparation, spectral analysis, and molecular modeling experiments on the new 3,4-annelated coumarin systems with bioactivity associated structural features are described. These provided the insight into the equilibrium of the respective tautomeric forms making possible the reconciliation of previously published spectral data with the structure assignments as well as the correction of erroneously established structures. The synthesized compounds were tested in a standard disk diffusion assay and displayed strong to moderate antimicrobial activity, with a promising new lead prototype compound (7-amino-9-hydroxy-5-oxa-7a,8,11-triazacyclopenta[b]phenanthren-6-one (5)) possessing greater activity that the antibiotics Ampicillin and Nystatin. Antioxidant capacities of the compounds, determined spectrophotometrically using a phosphomolybdenum method, were greater, and in the case of compound 5 four times the activity of α-tocopherol acetate.     

Machine learning for in silico virtual screening and chemical genomics: new strategies

Support vector machines and kernel methods belong to the same class of machine learning algorithms that has recently become prominent in both computational biology and chemistry, although both fields have largely ignored each other. These methods are based on a sound mathematical and computationally efficient framework that implicitly embeds the data of interest, respectively proteins and small molecules, in high-dimensional feature spaces where various classification or regression tasks can be performed with linear algorithms. In this review, we present the main ideas underlying these approaches, survey how both the "biological" and the "chemical" spaces have been separately constructed using the same mathematical framework and tricks, and suggest different avenues to unify both spaces for the purpose of in silico chemogenomics.     

2,5-二(2-氨基乙氧甲基)噻吩合成及抑菌活性

噻吩烷基胺及其衍生物对疟疾、麻风、真菌、病毒和某些肿瘤均有较强的药理活性[1～ 2 ] ,因此合成和开发这类新物质具有重要的意义。以前 ,由 2 噻吩甲醛合成的噻吩类衍生物药物较多[3] ,但对噻吩双取代衍生物的合成研究还未引起重视。因此 ,为了探索这类化合物的性质和抑菌效果。我们合成了未见文献报道的 2 ,5 二 ( 2 氨基乙氧甲基 )噻吩 ,通过多种测试手段 ,确定了它的组成结构 ,其合成路线如下 :1　实验部分1 1　仪器与试剂Ｎｉｃｏｌｅｔ1 70Ｓ红外光谱仪 (ＫＢｒ压片 ) ,ＰＥ 2 4 0Ｃ型元素分析仪 ,ＥＭ 360 60ＭＨｚ核磁共振仪。…     

Bridging coarse-grained models by jump-in-sample simulations

We present an efficient method to construct coarse-grained (CG) models from models of finer resolution. The method estimates the free energies in a generated sample of the CG conformational space and then fits the entire effective potential surface in the high-dimensional CG conformational space. A jump-in-sample algorithm that uses a random jumping walk in the CG sample is used to iteratively estimate the free energies. We test the method in a tetrahedral molecular fluid where we construct the intermolecular effective potential and evaluate the CG molecular model. Our algorithm for calculating the free energy involves an improved Wang-Landau (WL) algorithm, which not only works more efficiently than the standard WL algorithm, but also can work in high-dimensional spaces.     

Biology‐Oriented Synthesis of a Withanolide‐Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling

Biology‐oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans‐hydrindane dehydro‐δ‐lactone motif defines the characteristic scaffold of the steroid‐like withanolides, a plant‐derived natural product class with a diverse pattern of bioactivity. A withanolide‐inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell‐based assays that monitored biological signal‐transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened.     

New 3,4-Annelated Coumarin Derivatives: Synthesis, Antimicrobial Activity, Antioxidant Capacity, and Molecular Modeling

Summary.  The one pot reaction preparation, spectral analysis, and molecular modeling experiments on the new 3,4-annelated coumarin systems with bioactivity associated structural features are described. These provided the insight into the equilibrium of the respective tautomeric forms making possible the reconciliation of previously published spectral data with the structure assignments as well as the correction of erroneously established structures. The synthesized compounds were tested in a standard disk diffusion assay and displayed strong to moderate antimicrobial activity, with a promising new lead prototype compound (7-amino-9-hydroxy-5-oxa-7a,8,11-triazacyclopenta[b]phenanthren-6-one (5)) possessing greater activity that the antibiotics Ampicillin and Nystatin. Antioxidant capacities of the compounds, determined spectrophotometrically using a phosphomolybdenum method, were greater, and in the case of compound 5 four times the activity of α-tocopherol acetate.     

Unprecedented Combination of Polyketide Natural Product Fragments Identifies the New Hedgehog Signaling Pathway Inhibitor Grismonone

Pseudo-natural products (pseudo-NPs) are de novo combinations of natural product (NP) fragments that define novel bioactive chemotypes. For their discovery, new design principles are being sought. Previously, pseudo-NPs were synthesized by the combination of fragments originating from biosynthetically unrelated NPs to guarantee structural novelty and novel bioactivity. We report the combination of fragments from biosynthetically related NPs in novel arrangements to yield a novel chemotype with activity not shared by the guiding fragments. We describe the synthesis of the polyketide pseudo-NP grismonone and identify it as a structurally novel and potent inhibitor of Hedgehog signaling. The insight that the de novo combination of fragments derived from biosynthetically related NPs may also yield new biologically relevant compound classes with unexpected bioactivity may be considered a chemical extension or diversion of existing biosynthetic pathways and greatly expands the opportunities for exploration of biologically relevant chemical space by means of the pseudo-NP principle.