Role of Chemical Reactivity and Transition State Modeling for Virtual Screening

Author(s): Muthukumarasamy Karthikeyan, Renu Vyas, Sanjeev S. Tambe, Deepthi Radhamohan, Bhaskar D. Kulkarni

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 18 , Issue 7 , 2015

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Every drug discovery research program involves synthesis of a novel and potential drug molecule utilizing atom efficient, economical and environment friendly synthetic strategies. The current work focuses on the role of the reactivity based fingerprints of compounds as filters for virtual screening using a tool ChemScore. A reactant-like (RLS) and a product- like (PLS) score can be predicted for a given compound using the binary fingerprints derived from the numerous known organic reactions which capture the molecule-molecule interactions in the form of addition, substitution, rearrangement, elimination and isomerization reactions. The reaction fingerprints were applied to large databases in biology and chemistry, namely ChEMBL, KEGG, HMDB, DSSTox, and the Drug Bank database. A large network of 1113 synthetic reactions was constructed to visualize and ascertain the reactant product mappings in the chemical reaction space. The cumulative reaction fingerprints were computed for 4000 molecules belonging to 29 therapeutic classes of compounds, and these were found capable of discriminating between the cognition disorder related and anti-allergy compounds with reasonable accuracy of 75% and AUC 0.8. In this study, the transition state based fingerprints were also developed and used effectively for virtual screening in drug related databases. The methodology presented here provides an efficient handle for the rapid scoring of molecular libraries for virtual screening.

Keywords: Fingerprints, intermediates, metabolic pathways, product-like score, reactant-like score, reaction, screening, synthesis, virtual screening.

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Article Details

Year: 2015
Page: [638 - 657]
Pages: 20
DOI: 10.2174/1386207318666150703113135
Price: $65

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