scholarly journals Data enhanced Hammett-equation: reaction barriers in chemical space

2020 ◽  
Vol 11 (43) ◽  
pp. 11859-11868
Author(s):  
Marco Bragato ◽  
Guido Falk von Rudorff ◽  
O. Anatole von Lilienfeld
Keyword(s):  
Chemical Space ◽  
Hammett Equation ◽  
Molecular Scaffolds ◽  
Reaction Barriers ◽  
Original Approach

We generalize Hammett's original approach to predict potential energies of activation in non aromatic molecular scaffolds with multiple substituents.

scholarly journals ChemSpaX: Exploration of chemical space by automated functionalization of molecular scaffold

2022 ◽  
Author(s):  
Adarsh V. Kalikadien ◽  
Evgeny A Pidko ◽  
Vivek Sinha
Keyword(s):  
Chemical Space ◽  
Structure And Function ◽  
Molecular Scaffolds ◽  
Molecular Scaffold ◽  
And Function ◽  
Post Functionalization

Exploration of the local chemical space of molecular scaffolds by post-functionalization (PF) is a promising route to discover novel molecules with desired structure and function. PF with rationally chosen substituents...

scholarly journals A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids

2015 ◽  
Vol 51 (56) ◽  
pp. 11174-11177 ◽  
Author(s):  
Daniel J. Foley ◽  
Richard G. Doveston ◽  
Ian Churcher ◽  
Adam Nelson ◽  
Stephen P. Marsden
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Systematic Approach ◽  
Chemical Space ◽  
Building Blocks ◽  
Molecular Scaffolds ◽  
Disubstituted Amino Acids

A strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from four quaternary α-amino acid building blocks in only 49 synthetic operations, using six connective reactions. The ability of each scaffold to specifically target leadlike chemical space was demonstrated computationally.

scholarly journals ChemSpaX: Exploration of Chemical Space by Automated Functionalization of Molecular Scaffold

2021 ◽  
Author(s):  
Adarsh Kalikadien ◽  
Evgeny A. Pidko ◽  
Vivek Sinha
Keyword(s):  
Transition Metal ◽  
Chemical Space ◽  
Data Driven ◽  
Molecular Scaffolds ◽  
Molecular Scaffold ◽  
Automated Generation ◽  
Design And Optimization ◽  
Screening Design ◽  
Computational Screening ◽  
And Function

Exploration of the local chemical space of molecular scaffolds by post-functionalization (PF) is a promising route to discover novel molecules with desired structure and function. PF with rationally chosen substituents based on known electronic and steric properties is a commonly used experimental and computational strategy in screening, design and optimization of catalytic scaffolds. Automated generation of reasonably accurate geometric representations of post-functionalized molecular scaffolds is highly desirable for data-driven applications. However, automated PF of transition metal (TM) complexes remains challenging. In this work a Python-based workflow, ChemSpaX, that is aimed at automating the PF of a given molecular scaffold with special emphasis on TMcomplexes, is introduced. In three representative applications of ChemSpaX by comparing with DFT and DFT-B calculations, we show that the generated structures have a reasonable quality for use in computational screening applications. Furthermore, we show thatChemSpaXgenerated geometries can be used in machine learning applications to accurately predict DFT computed HOMO-LUMO gaps for transition metal complexes.ChemSpaXis open-source and aims to bolster and democratize the efforts of the scientific community towards data-driven chemical discovery.

scholarly journals Guided by Evolution: Biology-Oriented Synthesis of Bioactive Compound Classes

Synthesis ◽  
2018 ◽  
Vol 51 (01) ◽  
pp. 55-66 ◽  
Author(s):  
George Karageorgis ◽  
Herbert Waldmann
Keyword(s):  
Natural Products ◽  
Small Molecules ◽  
Chemical Space ◽  
Bioactive Compound ◽  
Molecular Architecture ◽  
Molecular Scaffolds ◽  
Biologically Relevant ◽  
Chemistry Research ◽  
Synthetic Methodologies

Biology-oriented-synthesis (BIOS), is a chemocentric approach to identifying structurally novel molecules as tools for chemical biology and medicinal chemistry research. The vast chemical space cannot be exhaustively covered by synthetic chemistry. Thus, methods which reveal biologically relevant portions of chemical space are of high value. Guided by structural conservation in the evolution of both proteins and natural products, BIOS classifies bioactive compound classes in a hierarchical manner based on molecular architecture and bioactivity. Biologically relevant scaffolds inspire and guide the synthesis of BIOS libraries, which calls for the development of suitable synthetic methodologies. These compound collections have enriched biological relevance, leading to the discovery of bioactive small molecules. These potent and selective modulators allow the study of complex biological pathways and may serve as starting points for drug discovery programs. Thus, BIOS can also be regarded as a hypothesis-generating tool, guiding the design and preparation of novel, bioactive molecular scaffolds. This review elaborates the principles of BIOS and highlights selected examples of their application, which have in turn created future opportunities for the expansion of BIOS and its combination with fragment-based compound discovery for the identification of biologically relevant small molecules with unprecedented molecular scaffolds.1 Introduction2 Structural Classification of Natural Products3 Implications and Opportunities for Biology-Oriented Synthesis4 Applications of Biology-Oriented Synthesis4.1 Chemical Structure and Bioactivity Guided Approaches4.2 Natural-Product-Derived Fragment-Based Approaches5 Conclusions and Outlook

Layered and ion implantation specimens as possible reference materials for the electron-probe microanalysis

1992 ◽  
Vol 50 (2) ◽  
pp. 1652-1653
Author(s):  
G. Remond ◽  
R.H. Packwood ◽  
C. Gilles ◽  
S. Chryssoulis
Keyword(s):  
Ion Implantation ◽  
Reference Materials ◽  
Analytical Techniques ◽  
Thin Film Deposition ◽  
Film Deposition ◽  
X Ray ◽  
Spatially Resolved ◽  
Analytical Expressions ◽  
Original Approach ◽  
Depth Concentration

Merits and limitations of layered and ion implanted specimens as possible reference materials to calibrate spatially resolved analytical techniques are discussed and illustrated for the case of gold analysis in minerals by means of x-ray spectrometry with the EPMA. To overcome the random heterogeneities of minerals, thin film deposition and ion implantation may offer an original approach to the manufacture of controlled concentration/ distribution reference materials for quantification of trace elements with the same matrix as the unknown.In order to evaluate the accuracy of data obtained by EPMA we have compared measured and calculated x-ray intensities for homogeneous and heterogeneous specimens. Au Lα and Au Mα x-ray intensities were recorded at various electron beam energies, and hence at various sampling depths, for gold coated and gold implanted specimens. X-ray intensity calculations are based on the use of analytical expressions for both the depth ionization Φ (ρz) and the depth concentration C (ρz) distributions respectively.

Forensic research of staff fraud

2020 ◽  
Vol 23 (5) ◽  
pp. 585-600
Author(s):  
V.A. Timchenko
Keyword(s):  
Effective Means ◽  
Criminal Activity ◽  
Diagnostic Techniques ◽  
Scientific Basis ◽  
Diagnostic Methods ◽  
Structural Units ◽  
Forensic Research ◽  
Economic Information ◽  
Commercial Organizations ◽  
Original Approach

Subject. This article deals with the issues of forensic diagnostics, which is an effective means of detecting, preventing and suppressing staff fraud. Objectives. The article aims to present an original approach to the development of methods of forensic diagnosis of staff fraud based on the modeling method. It is also intended to identify a structure of staff fraud patterns and justify the need to classify the staff fraud methods. Methods. For the study, I used the methods of comparative analysis, systematization, induction, and deduction. Results. The article defines approaches to the formation of diagnostic methods of staff fraud and presents typical inconsistencies that arise in economic information under the influence of fraudulent actions of staff. It describes some diagnostic techniques that can detect staff fraud elements that occur in certain ways of criminal activity. Conclusions and Relevance. The proposed original approach helps develop standard and specific methods for diagnosing staff fraud on a scientific basis. The provisions outlined in the article can serve as a basis for scholarly discussion, contribute to the effectiveness of research on counter-fraud in the field of personnel fraud, and can be applied to the practical activities of structural units and individuals whose task is to combat staff fraud in commercial organizations.

Russian Accounting Standard (PBU) 18/02: Principles on the balance method use

2020 ◽  
Vol 23 (12) ◽  
pp. 1356-1382
Author(s):  
E.V. Olomskaya ◽  
A.A. Aksent'ev
Keyword(s):  
Balance Method ◽  
Deferred Taxes ◽  
Accounting Standard ◽  
Scientific Methods ◽  
The Public ◽  
General Scientific ◽  
The Impact ◽  
Original Approach ◽  
Descriptive Method ◽  
Tax Accounting

Subject. This article discusses the methodological features of Russian Accounting Standard (PBU) 18/02 Income Tax Accounting when using the balance method to account for deferred taxes. It considers whether the clarification of permanent tax differences is justified, and it analyzes in detail the features of accounting for temporary differences and offers a visual and descriptive method for determining and correlating them in accounts. Objectives. The article aims to justify the reason for linking permanent tax differences to such accounting categories as Income and Expenses. It also aims to develop a methodological toolkit that simplifies the perception of the balance method and demonstrates the procedure for determining temporary differences. Methods. For the study, we used the methods of analysis, synthesis, observation, comparison, and other general scientific methods. Results. The article justifies the clarification of permanent differences from the position of accounting categories. It offers an original approach that helps visually classify temporary differences. The formalization of the balance method helped identify the logic of its reflection in accounting statements. Conclusions and Relevance. To ensure that accounting is not distorted due to the impact of taxation, it is necessary to develop a unified conceptual framework, as well as develop existing methods and introduce new ones that do not contradict the public concept of interaction between accounting and tax accounting. The research results are intended for training, scientific and practical activities of specialists in the field of accounting and audit, as well as students studying under this program, in order to study the features of applying the balance method for accounting for deferred taxes.

Total Synthesis of Axially-Chiral Cannabinols: A New Platform for Cannabinoid-Based Drug Discovery

2019 ◽  
Author(s):  
Primali Navaratne ◽  
Jenny Wilkerson ◽  
Kavindri Ranasinghe ◽  
Evgeniya Semenova ◽  
Lance McMahon ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Total Synthesis ◽  
Ground State ◽  
Chemical Space ◽  
Modern Medicine ◽  
The Novel ◽  
Pharmaceutical Development ◽  
Bioactive Component ◽  
Axially Chiral ◽  
New Directions

<div> <div> <div> <p>Phytocannabinoids, molecules isolated from cannabis, are gaining attention as promising leads in modern medicine, including pain management. Considering the urgent need for combating the opioid crisis, new directions for the design of cannabinoid-inspired analgesics are of immediate interest. In this regard, we have hypothesized that axially-chiral-cannabinols (ax-CBNs), unnatural (and unknown) isomers of cannabinol (CBN) may be valuable scaffolds for cannabinoid-inspired drug discovery. There are multiple reasons for thinking this: (a) ax-CBNs would have ground-state three-dimensionality akin to THC, a key bioactive component of cannabis, (b) ax-CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical development due to their ease of functionalization and stability, and (c) atropisomerism with respect to phytocannabinoids is unexplored “chemical space.” Herein we report a scalable total synthesis of ax-CBNs, examine physical properties experimentally and computationally, and provide preliminary behavioral and analgesic analysis of the novel scaffolds. </p> </div> </div> </div>

Metal-, and Organocatalyst-Free One-Pot Assembly of Chiral Aza-Tricyclic Molecules: Creating Six Contiguous Stereocenters from 2-D-Structures and an Amino Acid

2020 ◽  
Author(s):  
Dung Do
Keyword(s):  
Amino Acid ◽  
Chemical Space ◽  
Structural Diversity ◽  
Therapeutic Agents ◽  
Chiral Molecules ◽  
One Pot ◽  
Complex Molecules ◽  
Chiral Catalyst ◽  
Chiral Complex ◽  
Free Process

<p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.<sup>1</sup> Practically, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for desired reactions. As a result, developing a method that enables rapid assembly of chiral complex molecules under metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward route to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“subcatalyst”) dual role of the intermediate enhances </a><a>the coordinational proximity of the chiral substrate and catalyst</a> in the key Aza-Michael/Michael cascade resulting in a substantial steric discrimination and an excellent overall diastereoselectivity. Whereas the “subcatalyst” (hidden catalyst) is not present in the reaction’s initial components, which renders a chiral catalyst-free process, it is strategically produced to promote sequential self-catalyzed reactions. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules and aid for the quest to create next generation of therapeutic agents.</p>

Reaction-based Enumeration, Active Learning, and Free Energy Calculations to Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin Dependent Kinase 2 Inhibitors

2019 ◽  
Author(s):  
Kyle Konze ◽  
Pieter Bos ◽  
Markus Dahlgren ◽  
Karl Leswing ◽  
Ivan Tubert-Brohman ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Active Learning ◽  
Large Scale ◽  
Chemical Space ◽  
Population Based ◽  
Free Energy Calculations ◽  
Computational Technique ◽  
Cyclin Dependent Kinase ◽  
Energy Calculations

We report a new computational technique, PathFinder, that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. Coupling PathFinder with active learning and cloud-based free energy calculations allows for large-scale potency predictions of compounds on a timescale that impacts drug discovery. The process is further accelerated by using a combination of population-based statistics and active learning techniques. Using this approach, we rapidly optimized R-groups and core hops for inhibitors of cyclin-dependent kinase 2. We explored greater than 300 thousand ideas and identified 35 ligands with diverse commercially available R-groups and a predicted IC<sub>50</sub> < 100 nM, and four unique cores with a predicted IC<sub>50</sub> < 100 nM. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

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