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Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.

ABSTRACT: Biliary tract cancer (BTC) is constituted by a heterogeneous group of malignant tumors that may develop in the biliary tract, and it is the second most common liver cancer. Human ribonucleotide reductase M1 (hRRM1) has already been proven to be a potential BTC target. In the current study, a de novo design approach was used to generate novel and effective chemical therapeutics for BTC. A set of comprehensive pharmacoinformatics approaches was implemented and, finally, seventeen potential molecules were found to be effective for the modulation of hRRM1 activity. Molecular docking, negative image-based ShaEP scoring, absolute binding free energy, in silico pharmacokinetics, and toxicity assessments corroborated the potentiality of the selected molecules. Almost all molecules showed higher affinity in comparison to gemcitabine and naphthyl salicylic acyl hydrazone (NSAH). On binding interaction analysis, a number of critical amino acids was found to hold the molecules at the active site cavity. The molecular dynamics (MD) simulation study also indicated the stability between protein and ligands. High negative MM-GBSA (molecular mechanics generalized Born and surface area) binding free energy indicated the potentiality of the molecules. Therefore, the proposed molecules might have the potential to be effective therapeutics for the management of BTC.

SUBMITTER: Islam MA

PROVIDER: S-EPMC9496582 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.

Islam Md Ataul MA Barshetty Mayuri Makarand MM Srinivasan Sridhar S Dudekula Dawood Babu DB Rallabandi V P Subramanyam VPS Mohammed Sameer S Natarajan Sathishkumar S Park Junhyung J

Biomolecules 20220910 9

Biliary tract cancer (BTC) is constituted by a heterogeneous group of malignant tumors that may develop in the biliary tract, and it is the second most common liver cancer. Human ribonucleotide reductase M1 (hRRM1) has already been proven to be a potential BTC target. In the current study, a de novo design approach was used to generate novel and effective chemical therapeutics for BTC. A set of comprehensive pharmacoinformatics approaches was implemented and, finally, seventeen potential molecul ...[more]

PMID: 36139117

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Project description:We previously used a combination of continuous-wave (CW) and pulsed electron-nuclear double resonance (ENDOR) protocols to identify the types of protonated oxygen (OH(x)) species and their disposition within the Fe(III)/Fe(IV) cluster of intermediate X, the direct precursor of the essential diferric-tyrosyl radical cofactor of the beta2 subunit of Escherichia coli ribonucleotide reductase (RNR). We concluded that X contains the [(H(x)O)Fe(III)OFe(IV)] fragment (T model), and does not contain a mu-hydroxo bridge. When combined with a subsequent (17)O ENDOR study of X prepared with H(2)(17)O and with (17)O(2), the results led us to suggest that this fragment is the entire inorganic core of X. This has been questioned by recent reports, but these reports do not themselves agree on the core of X. One concluded that X possesses a di-mu-oxo Fe(III)/Fe(IV) core plus a terminal (H(2)O) bound to Fe(III) [e.g., Han, W.-G.; Liu, T.; Lovell, T.; Noodleman, L. J. Am. Chem. Soc. 2005, 127, 15778-15790]. The other [Mitic, N.; Clay, M. D.; Saleh, L.; Bollinger, J. M.; Solomon, E. I. J. Am. Chem. Soc. 2007, 129, 9049-9065] concluded that X contains only a single oxo bridge and postulated the presence of an additional hydroxo bridge plus a terminal hydroxyl bound to Fe(III). In this report we take advantage of improvements in 35 GHz pulsed ENDOR performance to reexamine the protonation state of oxygenic ligands of the inorganic core of X by directly probing the exchangeable proton(s) with (2)H pulsed ENDOR spectroscopy. These (2)H ENDOR measurements confirm that X contains an Fe(III)-bound terminal aqua ligand (H(x)O), but the spectra contain none of the features that would be required for the proton of a bridging hydroxyl. Thus, we confirm that X contains a terminal aqua (most likely hydroxo) ligand to Fe(III) in addition to one or two mu-oxo bridges but does not contain a mu-hydroxo bridge. The (2)H ENDOR measurements further demonstrate that this conclusion is applicable to both wild type and Y122F-beta2 mutant, and in fact we detect no difference between the properties of protons on the terminal oxygens in the two variants; likewise, (14)N ENDOR measurements of histidyl ligands bound to Fe show no difference between the two variants.

Dataset Information

Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.

Publications

Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.

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