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In silico design and evaluation of novel 5-fluorouracil analogues as potential anticancer agents.

ABSTRACT: 5-fluorouracil (5-FU) has been shown to have suffered from resistance which demands a solution entailing the development of 5-FU analogues. Our study aims to design a number of analogues of 5-FU and evaluate their effectiveness against thymidylate synthase (TS) in silico compared to parent 5-FU with an effort to obtain better hit(s). All the molecules were optimized by molecular mechanics method utilizing MM2 forcefield parameters. Molecular docking of these molecules against TS was performed to catch on the binding strength of these molecules, determination of binding energy & interaction types of each ligand-target complex as well as subsequent analysis. PRA10 showed highest binding affinity (-9.1 Kcal/mol). Although binding energy of PRA6 & PRA14 are slightly lower than PRA10, they can be of special interest since they interact with crucial amino acids for binding and exhibit substantial non-bonded interactions. Residue analysis revealed that Arg50A, Arg175B, Arg215A, Ser216A, Arg176B and Asn226A of TS active site were crucial for binding/interaction. The best scored drug candidates demonstrated considerable pharmacokinetic as well as druglike properties. The present study also revealed that PRA6, PRA10 and PRA14 can be potential anticancer drugs for further development.

SUBMITTER: Chowdhury SM

PROVIDER: S-EPMC7536301 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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<i>In silico</i> design and evaluation of novel 5-fluorouracil analogues as potential anticancer agents.

Chowdhury Surid Mohammad SM Hossain Md Nuruzzaman MN Rafe Md Rajdoula MR

Heliyon 20200901 9

5-fluorouracil (5-FU) has been shown to have suffered from resistance which demands a solution entailing the development of 5-FU analogues. Our study aims to design a number of analogues of 5-FU and evaluate their effectiveness against thymidylate synthase (TS) <i>in silico</i> compared to parent 5-FU with an effort to obtain better hit(s). All the molecules were optimized by molecular mechanics method utilizing MM2 forcefield parameters. Molecular docking of these molecules against TS was perfo ...[more]

PMID: 33033767

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Project description:This study reports the formation of 5-FU co-crystals with four different pharmacologically safe co-formers; Urea, Thiourea, Acetanilide and Aspirin using methanol as a solvent. Two fabrication schemes were followed i.e., solid-state grinding protocol, in which API and co-formers were mixed through vigorous grinding while in the other method separate solutions of both the components were made and mixed together. The adopted approaches offer easy fabrication protocols, no temperature maintenance requirements, no need of expensive solvents, hardly available apparatus, isolation and purification of the desired products. In addition, there is no byproducts formation, In fact, a phenomenon embracing the requirements of green synthesis. Through FTIR analysis; for API the N-H absorption frequency was recorded at 3409.02 cm-1 and that of -C[bond, double bond]O was observed at 1647.77 cm-1. These characteristics peaks of 5-FU were significantly shifted and recorded at 3499.40 cm-1 and 1649.62 cm-1 for 5-FU-Ac (3B) and 3496.39 cm-1 and 1659.30 cm-1 for 5-FU-As (4B) co-crystals for N-H and -C[bond, double bond]O groups respectively. The structural differences between API and co-crystals were further confirmed through PXRD analysis. The characteristic peak of 5-FU at 2θ = 28.79918o was significantly shifted in the graphs of co-crystals not only in position but also with respect to intensity and FWHM values. In addition, new peaks were also recorded in all the spectra of co-formers confirming the structural differences between API and co-formers. In addition, percent growth inhibition was also observed by all the co-crystals through MTT assay against HCT 116 colorectal cell lines in vitro. At four different concentrations; 25, 50, 100 and 200 µg/mL, slightly different trends of the effectiveness of API and co-crystals were observed. However; among all the co-crystal forms, 5-FU-thiourea co-crystals obtained through solution method (2B) proved to be the most effective growth inhibitor at all the four above mentioned concentrations.

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In silico design and evaluation of novel 5-fluorouracil analogues as potential anticancer agents.

Publications

<i>In silico</i> design and evaluation of novel 5-fluorouracil analogues as potential anticancer agents.

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