Background and features of emil, a system for database-aided bioanalogous structural transformation of bioactive compounds

Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and artificial intelligence?

“…There are additional benefits in encoding the transformations as reactions in that enumeration software can be used to convert "problem" molecules into potential solutions. This was originally recognized by Fujita with the development of EMIL [57] and then again in Abbott's Drug Guru software [58] where manually encoded reactions were used to capture medicinal chemistry experience. Extension of this type of approach via cyclic enumeration and scoring can create "evolutionary optimization" [59], [60].…”

Matched Molecular Pair Analysis in Drug Discovery: Methods and Recent Applications

“…Rather than relying on manual classification of molecular transformations for improving bioactivities, researchers are now extracting transformational knowledge data sets in computer-readable format and compiling them into databases of rules (e.g., the work of example-mediated innovation for lead evolution) . In 2005, the term molecular matched pair (MMP) was initially proposed by Kenny and Sadowski, and it has rapidly become a standard way for extracting medicinal chemistry knowledge to guide lead optimization. − Borrowing the concept from synthetic chemistry, an MMP is defined as a pair of compounds that differ from each other by only a small localized structural change.…”

“…A set of predefined molecular transformation methods has been used as the starting point on the basis of general transformation categories, such as Drug Guru, Buy me Grease, LEATHERFACE, ThricePairs, THINK, and RandSmi, 14,24−29 or on the basis of the application of bond cleavage rules, such as retrosynthetic combinatorial analysis procedure (RECAP) 13,28 2005 THINK, RandSmi Eli Lilly and Company in-house tools applying a series of predefined transformations and random permutations Leach et al 14 2006 LEATHERFACE, find_pairs AstraZeneca in-house programs providing a guide to optimizing several pharmaceutical properties Stewart et al 24 2006 Drug Guru A web platform for medicinal chemists to apply predefined transformation rules to query molecules Haubertin et al 29,30 2007 RECAP RECAP utilizes bond cleavage rules based on existing chemical knowledge, and applies to databases of bioactive molecules to identify transformations Cucurull-Sanchez 25 2010 Buy me Grease Buy me Grease is a Pfizer internal web-service runs on Pipeline Pilot server to quantify how substructual alterations can affect human liver microsome (HLM) clearance Dossetter 27 2010 ThricePairs An in-house software applies given matched molecular pair transformations to HLM data set to identify substituents that increase HLM stability maximum common substructure and the breaking of retrosynthetically interesting chemical substructures (BRICS). 29−31 For example, Drug Guru provides 186 common transformation rules covering 133 functional group transformations and 53 framework modifications.…”

Miticidal pyrethroids having an isobutyranilidoxime ether skeleton

“…allethrin, including imidomethylol esters,7h9 amidines10 and oxime ethers.11 Other structural modiÐcations in this direction are also feasible, because the optimum hydrophobicity varies depending on the route of administration as well as the type of biological e †ect. 12,13 In this study, we set out to prepare a new class of pyrethroids having a hydrophilic sub-structure such as an amidoxime ether, which had been suggested by a database-aided software system, EMIL,14 which releases candidate structures depending upon an input lead structure.15, 16 We report here compounds having one of the candidate structures that are not insecticidal but are miticidal against some house-dust mite species.…”