This study aimed to synthesize novel compounds as more effective carbonic anhydrase II inhibitors. For this purpose, 2-(3-methoxy4-(prop-2-yn-1-yloxy)phenyl)-4,5-diphenyl-1H-imidazole (3) was reacted ...with 3-methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde through the glyoxal reaction to produce a series of imidazole-based 1,2,3-triazoles 5a-f. The synthesized compounds were structurally confirmed using IR, 1H, and 13C NMR techniques. To evaluate their potential as inhibitors of carbonic anhydrase II enzyme, the synthesized compounds were tested via in vitro enzyme inhibition assay. Among the derivatives, compounds 5f and 5a exhibited the most promising inhibitory potential, with IC50 values of 0.025 ± 0.001 and 0.032 ± 0.003 µM, respectively. Both 5a and 5f derivatives have comparable inhibitory potential but 5f was found to be more potent than 5a. Molecular docking analysis revealed that compounds 5a and 5f displayed excellent binding scores of −8.0 and −8.4 kcal mol-1, respectively. The results were further validated by MD simulations. The RMSD analysis revealed the average values of 3.20 Å for the ligand-protein complex, 1.38 Å for the apoprotein, and 7.15 Å for the ligand molecule. Based on the chemical stability and biological importance, the compound 5f was identified as potential lead candidates for the development of more effective carbonic anhydrase II inhibitors.
A computer-assisted drug design (CADD) approach was utilized to design a new acetamido-N-(para-fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T-1-APFPB), ...following the pharmacophoric features of VEGFR-2 inhibitors. The stability and reactivity of T-1-AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T-1-AFPB's potential to bind with and inhibit VEGFR-2. The precise binding of T-1-AFPB against VEGFR-2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM-GBSA, and PCA studies. Then, T-1-AFPB (4-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamido)-N-(4-fluorophenyl)benzamide) was semi-synthesized and the in vitro assays showed its potential to inhibit VEGFR-2 with an IC
value of 69 nM (sorafenib's IC
was 56 nM) and to inhibit the growth of HepG2 and MCF-7 cancer cell lines with IC
values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T-1-AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T-1-AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T-1-APFPB providing it as a promising lead VEGFR-2 inhibitor for further development aiming at cancer therapy.
Protein kinases regulate cellular activities and make up over 60% of oncoproteins and proto-oncoproteins. Among these kinases, FLT3 is a member of class III receptor tyrosine kinase family which is ...abundantly expressed in individuals with acute leukemia. Our previous oxindole-based hit has a particular affinity toward FLT3 (IC
= 2.49 μM) and has demonstrated selectivity towards FLT3 ITD-mutated MV4-11 AML cells, with an IC
of 4.3 μM. By utilizing the scaffold of the previous hit, sixteen new compounds were synthesized and screened against NCI-60 human cancer cell lines. This leads to the discovery of a potent antiproliferative compound, namely
, with an average GI
value against leukemia and colon cancer subpanels equalling 3.39 and 5.97 µM, respectively. Screening against a specific set of 10 kinases that are associated with carcinogenesis indicates that compound
has a potent FLT3 inhibition (IC
= 36.21 ± 1.07 nM). Remarkably, compound
was three times more effective as a CDK2 inhibitor (IC
= 8.17 ± 0.32 nM) compared to sunitinib (IC
= 27.90 ± 1.80 nM). Compound
was further analyzed by means of docking and molecular dynamics simulation for CDK2 and FLT3 active sites which provided a rational for the observed strong inhibition of kinases. These results suggest a novel structural scaffold candidate that simultaneously inhibits CDK2 and FLT3 and gives encouragement for further development as a potential therapeutic for leukemia and colon cancer.
VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine ...analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA’s oral treatment didn’t show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.
A group of theobromine derivatives was designed based on the key pharmacophoric characteristics of VEGFR-2 inhibitors. HepG2 and MCF-7 cancer cell lines were used to test the obtained compounds for ...their in vitro anti-proliferative activities. Compound 15 (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(4-(1-(2-(4-hydroxybenzoyl)hydrazono)ethyl) phenyl)acetamide) was the most potent cytotoxic member against MCF-7 (IC50 = 0.42 µM) and HepG2 (IC50 = 0.22 µM). The effectiveness of VEGFR-2 inhibition was assessed for compound 15, and its IC50 value was calculated to be 0.067 µM. Additional cellular mechanistic investigations showed that compound 15 dramatically increased the population of apoptotic HepG2 cells in both early and late apoptosis. The investigation of apoptotic markers confirmed that compound 15 upregulated the levels of BAX (2.26-fold) and downregulated the levels of Bcl-2 (4.4-fold). The molecular docking investigations, MM-GPSA, PLIP studies, and MD simulations validated the potential of compound 15 to be a VEGFR-2 inhibitor. DFT calculations have been completed to comprehend how the electrical charge is distributed within compound 15 and to predict how it would bond to VEGFR-2. Lastly, ADMET prediction showed that the designed members have drug-like characteristics and minimal levels of toxicity. In conclusion, our in vitro and in silico investigations showed that compound 15 exhibited promising apoptotic anticancer potential through the suppression of VEGFR-2.
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•A new series of semi-synthetic theobromine derivatives has been designed and synthesized as VEGFR-2 inhibitors.•VEGFR-2 inhibitory activity and cytotoxic effect were assessed.•The effect on apoptosis, and apoptotic markers (BAX & Bcl2) was determined.•In silico docking, MD simulation, ADMET, and toxicity studies were carried out.
Opioids are a class of chemicals, naturally occurring in the opium poppy plant, and act on the brain to cause a range of impacts, notably analgesic and anti-inflammatory actions. Moreover, an ...overview was taken in consideration for SARS-CoV-2 incidence and complications, as well as the medicinal uses of opioids were discussed being a safe analgesic and anti-inflammatory drug in a specific dose. Also, our article focused on utilization of opioids in the medication of SARS-CoV-2. Therefore, the major objective of this study was to investigate the antiviral effect of opioids throughout an in silico study by molecular docking study to fifteen opioid compounds against SARS-CoV-2 main protease (PDB ID 6LU7, Mpro). The docking results revealed that opioid complexes potentially inhibit the Mpro active site and exhibiting binding energy (-11.0 kcal/mol), which is comparably higher than the ligand. Furthermore, ADMET prediction indicated that all the tested compounds have good oral absorption and bioavailability and can transport via biological membranes. Finally, Mpro-pholcodine complex was subjected to five MD (RMSD, RMSF, SASA, Rg, and hydrogen bonding) and two MM-PBSA, and conformational change studies, for 100 ns, confirmed the stability of pholcodine, as a representative example, inside the active site of Mpro.
The epidermal growth factor receptor (EGFR) plays a key role in the pathogenesis of cancers of different types. It has been shown that EGFR and EGF-like peptides are often overexpressed in human ...carcinomas and that these proteins can cause cell transformation both in vivo and in vitro. In order to design a new apoptotic EGFR inhibitor, we used the essential pharmacophoric structural properties of EGFR inhibitors. We started with the natural alkaloid, theobromine, to get a new semisynthetic N-cyclohexyl acetamide derivative (
T-1-NCA
).
T-1-NCA
was extensively examined computationally for its potential against the EGFR protein. We initially performed deep density functional theory (DFT) computations to validate its 3D structure. The electrostatic potential, global reactive indices, and total density of states anticipating a high degree of reactivity were also indicated by the DFT analyses. Second,
T-1-NCA
's propensity to bind and inhibit the EGFR protein was investigated and verified using structure-based computational investigations such as molecular docking against EGFR
WT
, molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments.
T-1-NCA
's computational ADME and toxicity profiles were examined before the synthesis, and its safety and general drug-likeness were anticipated. As a consequence,
T-1-NCA
was semi-synthesized to examine the proposed design and the in silico findings. In comparison with erlotinib,
T-1-NCA
suppressed EGFR
WT
in vitro with an IC
50
value of 24.25 nM. (5.87 nM). Furthermore,
T-1-NCA
suppressed the proliferation of A549 and HCT-116 malignant cell lines with IC
50
values of 40.20 and 34.05 µM, respectively, as compared to erlotinib, which had IC
50
values of 17.13 and 17.32 µM. Interestingly,
T-1-NCA
’s selectivity indices were 3.29 and 3.89 against the two cancer cell lines indicating its general safety. Finally, the apoptotic effects of
T-1-NCA
were confirmed by flow cytometry and RT-PCR through the significant increase of the levels BAX, Casp3, and Casp9 in addition to the significant decrease of Bcl-2 level.
Depending on the pharmacophoric characteristics of EGFR inhibitors, a new thieno2,3-dpyrimidine derivative has been developed. Firstly, the potential inhibitory effect of the designed compound ...against EGFR has been proven by docking experiments that showed correct binding modes and excellent binding energies of −98.44 and −88.00 kcal/mol, against EGFR wild-type and mutant type, respectively. Furthermore, MD simulations studies confirmed the precise energetic, conformational, and dynamic alterations that occurred after binding to EGFR. The correct binding was also confirmed by essential dynamics studies. To further investigate the general drug-like properties of the developed candidate, in silico ADME and toxicity studies have also been carried out. The thieno2,3-dpyrimidine derivative was synthesized following the earlier promising findings. Fascinatingly, the synthesized compound (4) showed promising inhibitory effects against EGFR
WT
and EGFR
T790M
with IC
50
values of 25.8 and 182.3 nM, respectively. Also, it exhibited anticancer potentialities against A549 and MCF-7cell lines with IC
50
values of 13.06 and 20.13 µM, respectively. Interestingly, these strong activities were combined with selectivity indices of 2.8 and 1.8 against the two cancer cell lines, respectively. Further investigations indicated the ability of compound 4 to arrest the cancer cells' growth at the G2/M phase and to increase early and late apoptosis percentages from 2.52% and 2.80 to 17.99% and 16.72%, respectively. Additionally, it was observed that compound 4 markedly increased the levels of caspase-3 and caspase-9 by 4 and 3-fold compared to the control cells. Moreover, it up-regulated the level of BAX by 3-fold and down-regulated the level of Bcl-2 by 3-fold affording a BAX/Bcl-2 ratio of 9.
Communicated by Ramaswamy H. Sarma
The results of the computational and the physicochemical studies of the encapsulation of resveratrol with β-cyclodextrin are presented here. At first, the molecular docking experiments predicted good ...binding. Several MD simulations and MM-PBSA experiments confirmed the reliable binding, showing optimal kinetics and energy. As an application, resveratrol inclusion complexes with β-cyclodextrin were obtained in an aqueous alcohol medium via microwave treatment. The results of thermographic measurements of the obtained clathrates using a differential scanning calorimeter are presented, and the obtained activation energy was calculated using the Ozawa–Flynn–Wall and Friedman methods, as well as nonparametric kinetics. The effect of complexation on the kinetic parameters of thermal destruction of the β-cyclodextrin–resveratrol inclusion complex was considered. The morphology of the surface of the obtained clathrate complexes was described using a scanning electron microscope. The spectral properties of the inclusion complex were characterized by FT-IR, 1H, and 13С NMR spectroscopic data. The obtained in silico, morphological, thermogravimetric, and spectral results confirmed the formation of the resveratrol–β-cyclodextrin complex. The antioxidant activities of the inclusion complex were determined to be 12.1 μg/mL, compared to 14.3 μg/mL for free resveratrol, indicating an improvement in the bioactivity.
Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential of the designed compound was revealed via a ...molecular docking study that showed the appropriate binding. Then, MD simulation (six studies) over a period of 100 ns was performed to confirm the precise binding and optimum energy. Additionally, MM-GBSA reaffirmed the perfect binding, exhibiting a total precise energy of −40.38 Kcal/Mol. The MM-GBSA experiments named the essential amino acids in the protein–ligand interaction, employing the binding energy decomposition and revealing the diversity of interactions of compound 7 inside the VEGFR-2 enzyme. As compound 7 is new, DFT experiments were utilized for molecular structure optimization. Additionally, the DFT results validated the coherent interaction of compound 7 with the VEGFR-2 enzyme. A good value of drug-likeness of compound 7 was acknowledged via in silico ADMET studies. Interestingly, the experimental in vitro prohibitory potential of compound 7 was better than that of sorafenib, demonstrating an IC50 value of 25 nM. Notably, the strong inhibitory effects of compound 10 against two cancer cell lines (MCF-7 and HCT 116) were established with IC50 values of 12.93 and 11.52 μM, disclosing high selectivity indexes of 6.7 and 7.5, respectively.
