Software‐aided structural elucidation in drug discovery

Ahlqvist, Marie; Leandersson, Carina; Hayes, Martin A.; Zamora, Ismael; Thompson, Richard A.

doi:10.1002/rcm.7364

Cited by 8 publications

(5 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These methods were applied (1) to elucidate binding mechanisms of substrates and inhibitors to monoamine transporter (MAT)2930313233343536 (2) to discover novel scaffolds of MAT inhibitors by virtual screening373839, and (3) to distinguish various molecular mechanisms of enantiomers binding to MAT4041. As one of these powerful computational methods, the molecular dynamics (MD) providing atomic description of protein dynamics and flexibility42434445 was employed to simulate the large scale motions of MAT274647. However, MD simulation has not yet been carried out to explore the binding of sNRIs to hNET.…”

mentioning

confidence: 99%

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

Zheng

Xue

Wang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

show abstract

mentioning

confidence: 99%

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

Zheng

Xue

Wang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Raw files of each study were processed with MassChemSite® and Compound Discoverer® (See selected settings in File S1, Section 3) in order to look for unknown compounds related to dimethachlor. At first, samples were classified according to the day after application of the commercial product, the dose and the type of sample.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, another software tool, MassChemSite®, was used in order to confirm the appearance of these metabolites and a reasonable structure can be proposed. This software provided the reaction as well as the mass spectrum, the parent and the proposed metabolite with the matches and mismatches for the full scan spectra and the HCD mass spectra. Using the last one, it compared the different ions and search for possible common ions, in order to corroborate if it came from the same family due to in most cases the parent compound having common fragments with its metabolites.…”

Section: Resultsmentioning

confidence: 99%

Degradation studies of dimethachlor in soils and water by UHPLC‐HRMS: putative elucidation of unknown metabolites

López‐Ruiz

Romero‐González

Ortega‐Carrasco

et al. 2019

Pest Management Science

View full text Add to dashboard Cite

BACKGROUND: The analytical control of the presence of dimethachlor and its metabolites in environmental samples, such as water and soils, is a main concern. Degradation of this pesticide has been evaluated in two types of soils and two different water conditions at two concentration levels. For that purpose, a new liquid chromatography-mass spectrometry method has been developed and putative identification of new metabolites has been performed. RESULTS: An analytical method based on ultra-high-performance liquid chromatography coupled to Orbitrap mass spectrometry (UHPLC-Orbitrap-MS) was developed to monitor the degradation of dimethachlor in environmental samples (water and soils). The degradation of dimethachlor in soils and groundwater samples has been monitored from 1 to 110 days after application of a plant protection product at two doses. Concentration of the parent compound slowly decreased in both matrices. DT 50 values ranged from 40 to 70 days. Some metabolites were detected in the commercial product and in the samples one day after the application of the plant protection product. In addition, three new metabolites were putatively identified during dimethachlor degradation by untargeted analysis. CONCLUSION: In this study, the degradation of dimethachlor into its metabolites has been studied in soils and water, using a UHPLC-Orbitrap-MS validated method. A putative elucidation of new metabolites of dimethachlor has been carried out applying HRMS and software tools. Degradation results allowed for understanding the behavior of dimethachlor in soils and water, and provided information regarding the possible risk of this pesticide and its metabolites to the ecosystem.

show abstract

“…A bibliographic study shows that only 8 Indonesian scientists contributed as the main principal authors (1 st author) in international publications in the theme of the new findings of natural products from Indonesian sponges and soft coral between 1994 and 2015 (Januar, 2016a). This becomes a problem because information on metabolites structure is important to evaluate the potency of new drug candidates (Ahlqvist et al, 2015). Therefore, a breakthrough is needed to increase new findings of natural products from Indonesian marine resources, particularly from soft corals species.…”

Section: Introductionmentioning

confidence: 99%

Logic Structure Determination (LSD) as a Computer Assisted Structure Elucidation (Case) for Molecular Structure Determination of Cytotoxic Cembranoids from Soft Coral

Januar

Zamani

Soedharma

et al. 2016

Squalen Bull. Marine Fisheries Postharvest Biotech.

View full text Add to dashboard Cite

Indonesian tropical soft corals are valuable resources that produce pharmacological cytotoxic cembranoids. However, the manual structure determination in these compounds requires adequate knowledge of organic chemistry. This study presents the application of Logic Structure Determination (LSD) as a freeware Computer Assisted Structure Elucidation (CASE) for automatic molecular structure determination of cembranoid compounds from soft corals species. 12 Nuclear Magnetic Resonance (NMR) datasets of cytotoxic cembranoids were used to evaluate the accuracy of LSD in generating the possible structures. The results of this study shows that LSD generated numerous possible molecular structures as the data input files were only derived from 2D-NMR HMQC (Heteronuclear MultipleQuantum Correlation), COSY (Homonuclear Correlation Spectroscopy), and HMBC (Heteronuclear Multiple Bond Correlation). The accuracy was significantly enhanced (only 2-4 possible cembranoid structures from each NMR dataset) with the addition of H2BC (Heteronuclear 2 Bond Correlation) experimental data. This may indicate that VLRC (Very Long-Range Correlations) significantly affects LSD capability. Furthermore, LSD with direct 2 bond NMR experimental data is a reliable CASE technique for cembranoid compounds identification. In general, this freeware-CASE has the potential to be applied on other types of small molecule compounds and may serves as a solution for elucidation bottleneck step in studies on Indonesian natural products.

show abstract

Software‐aided structural elucidation in drug discovery

Abstract: The software was shown to perform well for structural elucidation of metabolites from both phase I and phase II metabolism where the focus was on quickly understanding the rate-limiting metabolic step(s).

Cited by 8 publications

References 13 publications

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

Degradation studies of dimethachlor in soils and water by UHPLC‐HRMS: putative elucidation of unknown metabolites

Logic Structure Determination (LSD) as a Computer Assisted Structure Elucidation (Case) for Molecular Structure Determination of Cytotoxic Cembranoids from Soft Coral

Contact Info

Product

Resources

About