Development of a Fragment-Based in Silico Profiler for Michael Addition Thiol Reactivity

Abstract

The Adverse Outcome Pathway (AOP) paradigm details the existing knowledge that links the initial interaction between a chemical and a biological system, termed the molecular initiating event (MIE), through a series of intermediate events, to an adverse effect. An important example of a well-defined MIE is the formation of a covalent bond between a biological nucleophile and electrophilic compound. This particular MIE has been associated with various toxicological endpoints such as acute aquatic toxicity, skin sensitisation and respiratory sensitisation. This study has investigated the calculated parameters that are required to predict the rate of chemical bond formation (reactivity) of a dataset of Michael acceptors. Reactivity of these compounds towards glutathione was predicted using a combination of a calculated activation energy value (Eact, calculated using Density Functional Theory (DFT) calculation

Determining Cysteines Available for Covalent Inhibition Across the Human Kinome

“…More notably, in either scheme, the addition reaction is more favorable in a polar environment (high dielectric constants) 45 , especially in basic buffer that facilitates producing the thiolate group. 35 This makes sense as the high dielectric constant increases the dielectric screen between the general acid and the general base leading to the charge localization of the reaction groups. Thus, the transition state is further stabilized and the energy barrier reduced.…”

Development of a fragment-based in silico profiler for SN2 thiol reactivity and its application in predicting toxicity of chemicals towards Tetrahymena pyriformis

“…In doing this it is possible to calculate the energy difference between the reactants and transition states and/or intermediate structures computationally, this is termed the activation energy (Eact). Previous studies have shown calculated Eact to correlate well with reaction rate for Michael acceptors [11,12,14,19,20].…”

“…A recent study by the current authors showed it was possible to predict experimental reactivity (expressed as pRC50 values) for a set of Michael acceptors using a fragment-based in silico profiler where fragments are stored in a database with their respective, pre-calculated activated energy (Eact) values [20]. Fragments were developed for Michael acceptors by defining the length of alkyl chain beyond which further increases in chain length failed to significantly increase Eact.…”

“…The fragments developed for this are based on the largest group of chemicals investigated in a previous study by Roberts et al (SN2 compounds activated by a carbonyl electron-withdrawing group) [15]. This was achieved by adopting a similar method as applied previously to Michael acceptors [20].…”

COSMOS next generation – A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals

“…One of the new additions to the COSMOS NG is the ability to profile and group compounds by categories and pathways. Well-known chemical categories or mode-of-action (MoA) chemotypes are available for mutagenesis [66] , genotoxic carcinogens [67] , [68] , DNA binders [69] , [70] , [71] , protein binders [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , liver toxicity [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] and DART structural rules [88] . If the structure matches any of the categories defined by chemotype fragment, the structure will be associated with particular categories or rules.…”