Targeting natural compounds against HER2 kinase domain as potential anticancer drugs applying pharmacophore based molecular modelling approaches

Zeb

et al. 2019

JCM

Self Cite

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.

Section: Methodsmentioning

confidence: 99%

In Silico Study Probes Potential Inhibitors of Human Dihydrofolate Reductase for Cancer Therapeutics

Rana

Zeb

et al. 2019

JCM

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“…Molecular dynamics (MD) simulation studies have been extensively employed to delineate on the molecular motion, predict the enzyme mechanism and further to comprehend the complex assemblies. The MD simulations additionally disseminate knowledge on the nature of the small molecules with its protein at the atomistic level [36,37]. For the current investigation, MD was employed to assess the stability of the target and the ligand complexes which could be analysed according to the radius of gyration (Rg), root mean square deviation (RMSD), and the potential energies recruiting GROMACS v5.0.6.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Small Molecules That Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies

Baek

Park

et al. 2019

Cells

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Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors.

“…Molecular dynamics (MD) studies have been extensively employed to delineate on the molecular motion, predict the enzyme mechanism and further to comprehend on the complex assemblies. The MD simulations additionally disseminates knowledge on the nature of the small molecules with its protein at the atomistic level [31,32]. For the current investigation, MD was employed to assess the stability of the target and the ligand complexes and were analysed according to the root mean square deviation (RMSD), radius of gyration (Rg) and the potential energies recruiting GROningen MAchine for Chemical Simulations (GROMACS v5.0.6, ).…”

Section: Methodsmentioning

confidence: 99%

Natural Compound Modulates the Cervical Cancer Microenvironment—A Pharmacophore Guided Molecular Modelling Approaches

Doneti

Pawar

et al. 2018

JCM

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Cervical cancer is regarded as one of the major burdens noticed in women next to breast cancer. Although, human papilloma viruses (HPVs) are regarded as the principal causative agents, they require certain other factors such as oestrogen hormone to induce cervical cancer. Aromatase is an enzyme that converts androgens into oestrogens and hindering this enzyme could subsequently hamper the formation of oestrogen thereby alleviating the disease. Accordingly, in the current investigation, a structure based pharmacophore was generated considering two proteins bearing the Protein Data Bank (PDB) codes 3EQM (pharm 1) and 3S7S (pharm 2), respectively. The two models were employed as the 3D query to screen the in-house built natural compounds database. The obtained 51 compounds were escalated to molecular docking studies to decipher on the binding affinities and to predict the quintessential binding modes which were affirmed by molecular dynamics (MD) simulations. The compound has induced dose-dependent down regulation of PP2B, Nitric oxide synthase-2 (NOS2), and Interleukin 6 (IL-6) genes in the HeLa cells and has modulated the expression of apoptotic genes such as Bax, Bcl2, and caspases-3 at different concentrations. These results guide us to comprehend that the identified aromatase inhibitor was effective against the cervical cancer cells and additionally could server as scaffolds in designing new drugs.