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Electronic properties investigation of human dihydrofolate reductase complexes with ligands

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dc.contributor.authorNaumovich, V.
dc.contributor.authorGrishina, M.
dc.contributor.authorNovak, J.
dc.contributor.authorPathak, P.
dc.contributor.authorPotemkin, V.
dc.contributor.authorShahbaaz, M.
dc.contributor.authorAbdellattif, M.H.
dc.contributor.departmentMohd Shahbaaz: South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, Cape Town, Southen_US
dc.date.accessioned2024-03-21T15:38:57Z
dc.date.available2024-03-21T15:38:57Z
dc.date.epub2020-12-21
dc.date.issued2020
dc.description.abstractDespite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. In the focus of this study are complexes of human dihydrofolate reductase (hDHFR) with a series of known inhibitors bound in the active site. Further, a statistical analysis was performed to establish the relationships between a myriad electronic characteristics and IC50. The change in total volume and the change of own electrons number of hydrogen atoms in their atomic basins are identified as the descriptors correlating the most with the hDHFR inhibition potency. Additionally, two lipophilic parts of protein (Thr56, Ser59, Ile60 and Ile7, Val8, Ala9) were found, which act as a key factor in decreasing bioactivity. The depth analysis of intermolecular interactions showed that the interactions between water molecules and ligand play a crucial role in hDHFR inhibition. Furthermore, the molecular dynamics simulations were used for deeper understanding of the structural inhibition, each for 50 ns time scale in explicit water conditions. Thus, the AlteQ approach made it possible to determine the factors influencing the activity and evaluate them not only qualitatively, but also quantitatively.Communicated by Ramaswamy H. Sarma.en_US
dc.identifier.citationNaumovich V, Grishina M, Novak J, et al. Electronic properties investigation of human dihydrofolate reductase complexes with ligands. J Biomol Struct Dyn. 2022 Jul;40(11):4775-4790. doi: 10.1080/07391102.2020.1861985.en_US
dc.identifier.doi10.1080/07391102.2020.1861985
dc.identifier.journalJournal of Biomolecular Structure and Dynamicsen_US
dc.identifier.urihttps://www.tandfonline.com/doi/abs/10.1080/07391102.2020.1861985
dc.identifier.urihttps://doi.org/10.1080/07391102.2020.1861985
dc.identifier.urihttps://hdl.handle.net/11288/595584
dc.language.isoenen_US
dc.publisherTaylor and Francisen_US
dc.research.unitBioinformatics Capacity Developmenten_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subjectAlteQ approach
dc.subjectDHFR activity
dc.subjectDHFR-ligand complexes
dc.subjectElectron density
dc.subjectQuantum theory of atoms
dc.titleElectronic properties investigation of human dihydrofolate reductase complexes with ligandsen_US
dc.typeArticleen_US
dspace.entity.typePublication
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