Abstract:
:Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes thereduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of humanDHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cellproliferation. In the current study, ligand-based pharmacophore modeling identified and evaluatedthe critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generatedfrom known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS)deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features,including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and onehydrophobic (HYP). Hypo1 was validated using Fischer's randomization, test set, and decoy setvalidations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex,National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered byan absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test andLipinski's rule of five, where the drug-like hit compounds were identified. The hit compounds weredocked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67(docking score for the reference compound), clustering analysis, and hydrogen bond interactionswere identified. Furthermore, molecular dynamics (MD) simulation identified three compounds asthe best inhibitors of hDHFR with the lowest root mean square deviation (1.2 Å to 1.8 Å), hydrogenbond interactions with hDHFR, and low binding free energy (-127 kJ/mol to -178 kJ/mol). Finally,the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFRin human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoidarthritis chemotherapeutics.
journal_name
J Clin Medjournal_title
Journal of clinical medicineauthors
Rana RM,Rampogu S,Zeb A,Son M,Park C,Lee G,Yoon S,Baek A,Parameswaran S,Park SJ,Lee KWdoi
10.3390/jcm8020233subject
Has Abstractpub_date
2019-02-11 00:00:00issue
2issn
2077-0383pii
jcm8020233journal_volume
8pub_type
杂志文章abstract::Molecular monitoring of minimal residual disease (MRD) and BCR-ABL1 kinase domain (KD) mutation testing have a well consolidated role in the routine management of chronic myeloid leukemia (CML) patients, as they provide precious information for therapeutic decision-making. Molecular response levels are used to define ...
journal_title:Journal of clinical medicine
pub_type: 杂志文章,评审
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abstract:BACKGROUND:This retrospective study aimed to evaluate overall survival and the risk factors for mortality among Korean pediatric liver transplantation (LT) patients using data from two national registries: the Korean Network Organ Sharing (KONOS) of the Korea Centers for Disease Control and Prevention and the Korean Or...
journal_title:Journal of clinical medicine
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abstract::The incidence of melanoma has been increasing worldwide during recent decades. The objective of the study was to analyse the trends in incidence for in situ and invasive melanoma in the Spanish region of Catalonia during the period of 2008-2017. We designed a cross-sectional study with an age-period-cohort analysis of...
journal_title:Journal of clinical medicine
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abstract::Both pre-gestational maternal obesity (PGMO) and excessive gestational weight gain (EGWG) increase the risk of gestational diabetes mellitus (GDM). Here, we conducted a retrospective study to comparatively examine the relation between fetal birth weight (FW) and placental weight (PW) in PGMO (n = 100) compared to EGWG...
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更新日期:2020-06-03 00:00:00
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journal_title:Journal of clinical medicine
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journal_title:Journal of clinical medicine
pub_type: 杂志文章,评审
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更新日期:2021-01-22 00:00:00
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journal_title:Journal of clinical medicine
pub_type: 杂志文章,评审
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journal_title:Journal of clinical medicine
pub_type: 杂志文章,评审
doi:10.3390/jcm9113421
更新日期:2020-10-25 00:00:00
abstract::The authors wish to make the following corrections to this paper [...]. ...
journal_title:Journal of clinical medicine
pub_type: 已发布勘误
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更新日期:2019-03-20 00:00:00
abstract::Hypothermic machine perfusion (HMP) has been introduced as an alternative to static cold storage (SCS) in kidney transplantation, but its true benefit in the clinical routine remains incompletely understood. The aim of this study was to assess the effect of HMP vs. SCS in kidney transplantation. All kidney transplants...
journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm9072311
更新日期:2020-07-21 00:00:00
abstract::This article presents the technical aspects of the Polish fetal cardiac interventions (FCI) program, including preparation of the team and modifications in the technique of the procedure that aim to increase its safety for the mother and the fetus. Over 9 years, 128 FCI in 113 fetuses have been performed: 94 balloon a...
journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm9092888
更新日期:2020-09-07 00:00:00
abstract::The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Cli...
journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm9061984
更新日期:2020-06-24 00:00:00
abstract::The aim of this paper was to provide insights into alcohol misuse within UK veterans to inform as to whether their presentations differ from the general public. This was done by exploring differences in the severity of alcohol misuse between UK veterans and the general public admitted to a general NHS hospital over an...
journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm5110095
更新日期:2016-11-02 00:00:00
abstract:BACKGROUND:Psoriasis is a chronic inflammatory disease which affects the body far beyond the skin. Whereas there is solid evidence that chronic skin inflammation in psoriasis drives cardiovascular disease, the impact on renal impairment and acute kidney injury (AKI) is still unclear. We aimed to analyze the impact of p...
journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm9093004
更新日期:2020-09-17 00:00:00
abstract::Most human papillomavirus (HPV) antiviral strategies have focused upon inhibiting viral DNA replication, but it is increasingly apparent that viral DNA levels can be chemically controlled by approaches that promote its instability. HPVs and other DNA viruses have a tenuous relationship with their hosts. They must repl...
journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm4020204
更新日期:2015-01-01 00:00:00
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journal_title:Journal of clinical medicine
pub_type: 杂志文章
doi:10.3390/jcm7100296
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journal_title:Journal of clinical medicine
pub_type: 杂志文章
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更新日期:2020-11-25 00:00:00
abstract::Intravenous lipid emulsions are an essential component of parenteral nutrition regimens. Originally employed as an efficient non-glucose energy source to reduce the adverse effects of high glucose intake and provide essential fatty acids, lipid emulsions have assumed a larger therapeutic role due to research demonstra...
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journal_title:Journal of clinical medicine
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更新日期:2018-02-09 00:00:00
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更新日期:2018-10-05 00:00:00
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