The essential pharmacophoric structural properties were applied to design a new derivative of theobromine as an antiangiogenic EGFR inhibitor. The designed candidate is a (para-nitrophenyl)acetamide ...derivative of the natural alkaloid, theobromine (T-2-PNPA). The potentialities of T-2-PNPA to inhibit the EGFR protein were studied computationally in an extensive way. Firstly, the molecular docking against EGFRsup.WT and EGFRsup.T790M demonstrated T-2-PNPA's capabilities of binding with the targeted receptors. Then, the MD experiments (for 100 ns) illustrated through six different studies the changes that occurred in the energy as well as in the structure of EGFR-T-2-PNPA complex. Additionally, an MM-GBSA analysis determined the exact energy of binding and the essential residues. Furthermore, DFT calculations investigated the stability, reactivity, and electrostatic potential of T-2-PNPA. Finally, ADMET and toxicity studies confirmed both the safety as well as the general likeness of T-2-PNPA. Consequently, T-2-PNPA was prepared for the in vitro biological studies. T-2-PNPA inhibited EGFRsup.WT and EGFRsup.T790M with ICsub.50 values of 7.05 and 126.20 nM, respectively, which is comparable with erlotinib activities (5.91 and 202.40, respectively). Interestingly, T-2-PNPA expressed cytotoxic potentialities against A549 and HCT-116 cells with ICsub.50 values of 11.09 and 21.01 µM, respectively, which is again comparable with erlotinib activities (6.73 and 16.35, respectively). T-2-PNPA was much safer against WI-38 (ICsub.50 = 48.06 µM) than erlotinib (ICsub.50 = 31.17 µM). The calculated selectivity indices of T-2-PNPA against A549 and HCT-116 cells were 4.3 and 2.3, respectively. This manuscript presents a new lead anticancer compound (T-2-PNPA) that has been synthesized for the first time and exhibited promising in silico and in vitro anticancer potentialities.
•Superimposition docking studies revealing similarity in binding modes of Patuletin and Remdesivir against the RdRp.•MD simulations (200 ns) confirming stability and optimal changes.•MM-GBSA and 3D ...binding interactions analysis showing favorable and stable binding.•PCAT providing insights into dynamic behavior.•In vitro assays demonstrating exceptional potency with superior efficacy and safety margin of Patuletin over Remdesivir against the RdRp and SARS-CoV-2.
In the pursuit of identifying effective inhibitors against SARS-CoV-2, we conducted a detailed investigation into the binding interactions and inhibitory potential of Patuletin targeting the RNA-Dependent RNA Polymerase (RdRp), comparing it with the well-known anti-RdRp agent, Remdesivir. Superimposition molecular docking studies uncovered a high degree of similarity in binding modes between Patuletin and Remdesivir within the active site of the RdRp. MD simulations (RMSD, RMSF, RG, SASA, hydrogen bonding) over a 200 ns trajectory provided valuable insights into the binding and interactions of Patuletin and RdRp comparing Remdesivir. These simulations validated the correct binding and optimum changes in both energetic and dynamic aspects, confirming the stability of the Patuletin-RdRp complex comparing the Remdesivir-RdRp complex. Further, the MM-GBSA technique revealed favorable binding energies, with Patuletin displaying a significantly lower value (-4.24 kcal/mol) compared to Remdesivir (-2.15 kcal/mol), affirming the robustness of Patuletin-RdRp binding. The MM-GBSA analysis additionally examined the binding energetic components, revealing a high degree of similarity between Patuletin and Remdesivir. 3D binding interactions were investigated through ProLIF and PLIP studies reinforcing the stable binding observed in the simulations. Principal component analysis of trajectories (PCAT) studies were employed to discern coordinated motions within the evaluated systems, providing additional perspectives on the dynamic behavior of the Patuletin-RdRp complex. In vitro assays demonstrated Patuletin's exceptional inhibitory potency against the RdRp, with an IC50 of 248 nM, far surpassing Remdesivir, which exhibited an IC50 of 20 µM. Interestingly, the in vitro IC50 against SARS-CoV-2 values further supported the superior efficacy of Patuletin (0.476 µg/ml) over Remdesivir (10.86 µg/ml). Furthermore, the viral selectivity index (SI) values highlighted the remarkable safety margin of Patuletin (SI: 790.76) compared to Remdesivir (SI: 5.87), underscoring the potential of Patuletin as a safer and more potent therapeutic agent against SARS-CoV-2. In conclusion, our comprehensive analysis presents Patuletin as a promising candidate for further exploration as a potent inhibitor of SARS-CoV-2 RdRp, offering valuable insights for the development of effective anti-COVID-19 therapies.
•Synthesis of alkyl substituted thiourea and its characterization.•Single crystal XRD analysis.•In-Vitro carbonic anhydrase inhibition studies.•Computational studies including DFT, Molecular docking ...and ADMET Analysis.
Carbonic anhydrases (CAs) representing the class of metalloenzymes are expressed widely and play a crucial role in various physiological and pathological processes. The Alkyl substituted Acyl Thiourea was synthesized and characterized by NMR spectroscopic technique. Single crystal X-ray diffraction was applied to determine the molecular and crystal structures. Synthesized compound crystallized in monoclinic system P 21/c space group. Intermolecular N–H···S hydrogen bonds and Intramolecular N–H···O hydrogen bond were found in crystal structure. H … H interactions have major contributions in crystal packing as depicted by Hirshfeld surface analysis. No large cavity was observed during void volume analysis in the crystal packing. Stabilization was dominated via the dispersion energy contributions in the synthesized compound. In Vitro analysis showed that synthesized compound inhibited the carbonic anhydrase activity to an appreciable extent. Quantum mechanical descriptors were calculated using DFT studies. In molecular docking, reactive parts of the synthesized molecule contributed in forming the hydrogen bond with receptor protein target. Finally, ADMET Analysis were performed to assess the drug-like behavior of synthesized compound. Carbonic Anhydrase enzyme inhibitor of pharmaceutical significance can be developed using the synthesized molecule ES-2 as a lead molecule.
·A new series of new thiadiazol derivatives has been designed and synthesized as VEGFR-2 inhibitors.·VEGFR-2 inhibitory activity and cytotoxic effect were assessed.·The effect on cell cycle and ...apoptosis was determined.·In silico docking, MD simulation, ADMET, and toxicity studies were carried out.
The presented study reports the synthesis, in silico and in vitro evaluations of a series of novel thiadiazole derivatives designed with the pharmacophoric features of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) inhibitors. A comprehensive assessment against MCF-7 and HepG2 cancer cell lines revealed promising inhibitors, particularly, N-(4-((E)-1-(((Z)-5-acetyl-3-(2-chlorophenyl)-1,3,4-thiadiazol-2(3H)-ylidene) hydrazono) ethyl) phenyl)-4-chlorobenzamide (compound 22) exhibited a significantly low half-maximal inhibitory concentration (IC50) value against both MCF-7 and HepG2 cells of 0.03 µM and 0.39 µM, respectively. The rest of compounds exhibited also significant IC50 values against MCF-7 and HepG2 cells of (0.07–4.7 µM) and (0.12–8.75 µM), respectively. Furthermore, compound 22 displayed a VEGFR-2 inhibitory activity (VEGFR-2 = 0.042 µM) comparable to the established inhibitor sorafenib (VEGFR-2 = 0.041 µM). Detailed cell cycle analysis demonstrated that compound 22 induced a G0-G1 phase arrest of the MCF-7 cells (71.33 %), indicative of its potential to modulate cell cycle progression. Notably, compound 22 also exhibited a substantial increase in apoptosis in the MCF-7 cells, particularly in early (22.04 %) and late stages (13.94 %), underscoring its remarkable pro-apoptotic effect. Additionally, Compound 22 demonstrated a notable decrease in the migratory ability and wound healing capacity of MCF-7 cells. Computational studies, including molecular docking, revealed high binding affinities. Over a 200 ns MD simulation, the VEGFR-2-compound 22 complex initially displayed a rapid increase in RMSD followed by stability around 3.5 Å due to ligand conformational change while maintaining stable protein binding. This was confirmed by RMSF, SASA, RoG, and hydrogen bonding analysis. MM-GBSA, ProLIF, PCAT and FEL studies confirmed VEGFR-2-compound 22 complex binding at both dynamic and energetic levels. The computational ADMET studies demonstrated favorable pharmacokinetic properties. Furthermore, Density Functional Theory (DFT) studies confirmed the reactivity and stability of compound 22. These comprehensive findings underscore the potential of compound 22 as a lead candidate for further investigation in the development of VEGFR-2-targeted anticancer agents.
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•A new thiadiazole analogue (TDA) was designed to mimic VEGFR-2 inhibitors.•Significant VEGFR-2 inhibition was observed (IC50: 0.283 µM).•TDA showed Potent cytotoxicity and selectivity against breast ...and hepatic cancer cell lines.•TDA induced G0-G1 phase arrest, induced apoptosis and inhibited cancer cells migration and healing.•MD simulations (200 ns), MM-GBSA, PCAT and DFT studies confirmed stable binding and reactivity of TDA.
In this work, a new thiadiazole analogue (TDA) was designed with the intention of incorporating key features of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) inhibitors, and then was examined computationally and experimentally. In vitro (cytotoxicity on MCF-7, HepG2 and WI-38 cell lines, in vitro VEGFR-2 assay, cell cycle analysis, apoptosis assays, RT-PCR, and migration studies), in addition to in silico (molecular docking, ADMET, MD simulations and DFT studies) were conducted. Prior to synthesis, docking and ADMET studies yielded predictions indicating favorable activity and drug likeness. After synthesis, the results demonstrated promising inhibitory activity of TDA on MCF-7 and HepG2 cancer cell lines. These results were notably close to those of sorafenib. The in vitro VEGFR-2 assay revealed significant inhibition, with an IC50 value of 0.283 µM. Selectivity studies indicated a favorable safety profile, with reduced toxicity towards normal lung cells (WI-38). Cell cycle analysis of TDA revealed a significant arrest in the G0-G1 phase, compared to the control group. Apoptosis assays demonstrated a considerable increase in programmed cell death, particularly in the early stages as opposed to the control group. Additionally, there was a notable increase in the expression of the pro-apoptotic gene Bax and a downregulation of the anti-apoptotic gene Bcl2 in MCF-7 cells treated with TDA. TDA also exhibited an anti-angiogenic potential through decreasing the abilities of the MCF-7 cells to migrate and heal. Computationally, various MD simulations studies indicated stable interactions between TDA and VEGFR-2 over 200 ns on both mechanical and energetic levels. DFT studies confirmed reactivity and stability of TDA. These comprehensive findings emphasize TDA’s potential as a multi-targeted candidate for further development in cancer therapy. The promising inhibitory activity, favorable safety profile, and mechanistic insights highlight TDA as a noteworthy contender through further in vivo studies and modifications.
Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild ...(EGFRsup.WT; PDB: 4HJO) and mutant (EGFRsup.T790M; PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an ICsub.50 value of 17.23 nM for EGFR inhibition besides ICsub.50 values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (ICsub.50 = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis.
The current research outlines the synthesis of benzyl 4- (4-chlorophenylamino) -1-(4-chlorophenyl) -2,6-bis(4-chlorophenyl) -1,2,5,6-tetrahydropyridine -3-carboxylate. The title compound was ...crystallized in the monoclinic space group P21/n with Z = 4 and unit cell parameters a = 13.6684 Å (8), b = 9.1256 Å (4), c = 14.0839 Å (8), = 111.168 (7)°, and V = 1638.18 (17)°. The six-membered non-planar ring is shaped like a boat. Intermolecular C–H···Cl hydrogen bonds connect molecules in a three-dimensional crystal framework. The most significant contributions to crystal packing, according to the Hirshfeld surface investigation of the crystal structure, are from H ··· H (35.3%), H... Cl/Cl... H (27.0%), and H ··· C/C ··· H (21.8%). As a result, van der Waals interactions take precedence in crystal packing. In-vitro studies suggested this compound has better IC50 value of 0.588 ± 0.09 µM against MAO-A. In silico investigations, such as molecular docking, demonstrated that this molecule possessed exceptionally high Monoamine Oxidase A and Monoamine Oxidase B activity, with a binding energy value of -32.504 kJ/mol. Furthermore, Density functional theory (DFT) analyses supported these findings and suggested derivative 4 as a potential 'lead' molecule in pharmaceutical discovery and development.
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The current study included density function theory calculations, molecular docking studies, SeeSAR analysis, molecular dynamics studies and assessments of the absorption, distribution, metabolism, ...excretion and toxicity properties (ADMET) of N-(4-acetyl-4,5-dihydro-5-(7,8,9-substituted-tetrazolo1,5-a acetamides of -quinolin-4-yl)-1,3,4-thiadiazol-2-yl) that is 4a-j. These derivatives have previously been identified as anticancer agents against a human cervical cancer cell line. The primary goal of this work is to assess the potential of these derivatives as caspase-3 inhibitors using extensive computational analysis. The binding interactions of these compounds with caspase-3 protein (PDB ID: 4JJ8) were found and all compounds demonstrated strong binding interactions within the active pocket of the targeted protein. Interestingly, derivative 4e showed maximum potential and was found to have the strongest interactions with a binding energy of -29.6 kJ/mol. Furthermore, the findings were discovered to be in comparison with the reference drug, adriamycin (-26.5 kJ/mol). In addition to molecular docking, ADMET and simulation studies were carried out to determine their safety profiles, with the results correlating to molecular docking investigations. Finally, SeeSAR analysis and molecular dynamics simulation investigations were carried out. In conclusion, this molecule may be a "lead candidate' for making a more powerful caspase-3 inhibitor that can be used in tumors where the levels of caspase-3 are aberrantly high.
This work presents the synthesis and
in vitro
, and
in silico
analyses of new thiadiazole derivatives that are designed to mimic the pharmacophoric characteristics of vascular endothelial growth ...factor receptor-2 (VEGFR-2) inhibitors. A comprehensive evaluation of the inhibitory properties of the synthesized thiadiazole derivatives against the cancer cell lines MCF-7 and HepG2 identified several auspicious candidates. Among them, compound
14
showed remarkably low IC
50
values of 0.04 μM and 0.18 μM against MCF-7 and HepG2, respectively. VEGFR-2 inhibitory evaluation of compound
14
revealed a promising IC
50
value in the nanomolar range (103 nM). Further examination of the cell cycle revealed that compound
14
has the ability to stop the progression of the cell cycle in MCF-7 cells
via
G0-G1 phase arrest. Interestingly, compound
14
also demonstrated a noteworthy pro-apoptotic effect in MCF-7 cells, with notable increases in early apoptosis (16.53%) and late apoptosis (29.57%), along with a slight increase in the population of necrotic cells (5.95%). Furthermore, compound
14
showed a significant drop in MCF-7 cells' ability to migrate and heal wounds. Additionally, compound
14
promoted apoptosis by boosting BAX (6-fold) while lowering Bcl-2 (6.2-fold). The binding affinities of the synthesized candidates to their target (VEGFR-2) were confirmed by computational investigations, including molecular docking, principal component analysis of trajectories (PCAT), and molecular dynamics (MD) simulations. Additionally, compound
14
's stability and reactivity were investigated using density functional theory (DFT). These thorough results highlight compound
14
's potential as a lead contender for additional research in the creation of anticancer drugs that target VEGFR-2. This work establishes a foundation for promising thiadiazole derivatives for future therapeutic developments in anticancer- and angiogenesis-related scientific fields.
This work presents the synthesis and
in vitro
, and
in silico
analyses of new thiadiazole derivatives that are designed to mimic the pharmacophoric characteristics of vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.
