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Evaluating enzymatic synthesis of small molecule drugs

Paper ID Volume ID Publish Year Pages File Format Full-Text
31484 44800 2016 10 PDF Available
Title
Evaluating enzymatic synthesis of small molecule drugs
Abstract

•Biosynthetic pathways for small molecule drugs were simulated with the BNICE program.•Pathways connected known metabolites to drug products with purely enzymatic based chemistry.•Biochemical routes found for molecules with no known prior evidence of biosynthetic feasibility.•Enzymes identified for every predicted reaction based on chemical similarity.

There have been many achievements in applying biochemical synthetic routes to the synthesis of commodity chemicals. However, most of these endeavors have focused on optimizing and increasing the yields of naturally existing pathways. We sought to evaluate the potential for biosynthesis beyond the limits of known biochemistry towards the production of small molecule drugs that do not exist in nature. Because of the potential for improved yields compared to total synthesis, and therefore lower manufacturing costs, we focused on drugs for diseases endemic to many resource poor regions, like tuberculosis and HIV. Using generalized biochemical reaction rules, we were able to design biochemical pathways for the production of eight small molecule drugs or drug precursors and identify potential enzyme-substrate pairs for nearly every predicted reaction. All pathways begin from native metabolites, abrogating the need for specialized precursors. The simulated pathways showed several trends with the sequential ordering of reactions as well as the types of chemistries used. For some compounds, the main obstacles to finding feasible biochemical pathways were the lack of appropriate, natural starting compounds and a low diversity of biochemical coupling reactions necessary to synthesize molecules with larger molecular size.

Keywords
Metabolic engineering; Computational biology; Predictive biochemistry; Pharmaceutical production; Drug synthesis
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Publisher
Database: Elsevier - ScienceDirect
Journal: Metabolic Engineering - Volume 33, January 2016, Pages 138–147
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
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Full-text PDF Download
Online Support
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