Davood Gheidari

Myeloid cell leukemia-1 (Mcl-1) is a key anti-apoptotic protein that drives resistance to chemotherapy, making it a critical oncology target.

A series of novel derivatives of 3-(arylamino) quinazoline-2,4(1 H ,3 H )-dione were synthesized with moderate to good yields (20%−70%) using t -butyl hydroperoxide (TBHP) and iodine. Their efficacy against MutT homologue 1 (MTH1) was evaluated using in silico methods. Density functional theory (DFT) analysis, utilizing the B3LYP/6-311G (2df, p) basis set, indicated a promising reactivity profile for the synthesized compounds. The highest occupied molecular orbital (HOMO) regions associated with the phenylhydrazine group serve as sites for electron donation, functioning as electron-rich nucleophiles. Docking analysis with MTH1 enzymes revealed that all compounds exhibited docking scores ranging from −5.77 to −7.24, indicating favorable binding affinities. Among these, compound (3d) , with an energy of −7.24 kcal/mol, demonstrated the strongest binding affinity. Importantly, the Generalized Born and Surface Area Solvation (MM-GBSA) rescoring aligned with the docking data, reinforcing the reliability of the predicted binding modes and highlighting these compounds as promising MTH1 inhibitors. Molecular dynamics (MD) simulations indicated that Tyr7, Thr8, Lys23, and Trp117 exhibited a notably high interaction fraction, suggesting that these residues might be critical for the binding affinity of compound (3d) . The analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties indicated that all compounds possess a favorable pharmacological profile and comply with Lipinski’s Rule of Five (Ro5), as well as the Ghose, Veber, and Egan rules. Additionally, they are capable of human intestinal absorption (HIA) and exhibit no liver toxicity, whereas BAY-707 is anticipated to exhibit hepatotoxicity.

Tropomyosin receptor kinases (TRKs) play a crucial role in nerve development, and their dysregulation due to genetic alterations, such as NTRK fusions, has been linked to various cancers. Recently, TRKs have emerged as effective therapeutic targets. However, resistance to these therapies presents significant challenges. In this study, a series of pyrazolo[3,4-b]pyridine derivatives were analyzed to generate pharmacophore-based models, conduct molecular docking, perform molecular dynamics (MD) simulations, and evaluate absorption, distribution, metabolism, excretion, and toxicity (ADMET). The generated pharmacophore hypothesis, ADRR_1, identified essential characteristics required for biological activity. Molecular docking was carried out on 37 ligands, yielding docking scores ranging from −12.672 to −14.169 kcal/mol. The best fit was observed for ligand L5, which formed five conventional hydrogen bonds with residues Glu546, Met620, Lys627, and Lys572. Additionally, three carbon-hydrogen bonds were established between the pyrazolo[3,4-b]pyridine moiety and residues Gly623, Glu618, and Asp703. MD simulations further confirmed the stability of the TRKA-L5 complex, underscoring the robust interactions between L5 and the target protein. The virtual screening study used 453 ligands from the ZINC database and identified the hit ligand ZINC000013331109, which exhibited a docking score of −10.775 kcal/mol and demonstrated good binding affinity with key amino acids. All screened ZINC hits adhered to the Lipinski Rule of Five (Ro5), and notably, ZINC000013331109 did not exhibit hepatotoxicity, unlike the top-scoring ligands and entrectinib, which were associated with liver toxicity. This study highlights the potential of ZINC000013331109 as a promising candidate for TRKA inhibition. Further research is warranted to explore the efficacy and safety of this ligand in clinical settings.

Introduction: Psoriasis is a chronic, immune-mediated condition that affects approximately 100 million individuals worldwide. Interleukin 23 (IL-23) serves as a crucial pro-inflammatory cytokine in the pathogenesis of chronic inflammatory diseases associated with psoriasis. Monoclonal antibody therapies targeting IL-23 inhibit the overactive cytokine signaling that contributes to chronic inflammation across various organ systems. Over the past decade, IL-23 inhibitors have gained significant prominence in the treatment of psoriasis. Natural products have emerged as potential modulators of IL-23 activity, particularly in the context of inflammatory diseases such as inflammatory bowel disease (IBD). Several well-characterized phytochemicals, including sulforaphane, resveratrol, and curcumin, have demonstrated efficacy in inhibiting the production and function of Th17 cells, which are regulated by IL-23. However, the exploration of natural products specifically related to psoriasis has been limited.Methods: This study aimed to identify novel candidates derived from natural products for the treatment of psoriasis. To achieve this, 60,000 natural compounds were filtered according to the rule of five (Ro5) and obtained from the ZINC database. These ligands underwent high-throughput virtual screening (HTVS) in molecular docking studies against the IL-23 receptor. The top 50 ligands were subsequently re-evaluated using standard precision (SP), and for enhanced accuracy, the top 19 from the SP protocol were further screened using the extra precision (XP) protocol.Results and Discussion: The computational screening revealed that the docking energy values for the nineteen ligands binding to the target enzyme ranged from -3.669 to -7.143 kcal/mol. Among these, ligand 1 (L1) exhibited the highest binding energy at -7.143 kcal/mol with IL-23. Molecular dynamics (MD) simulation further confirmed the stability of the IL-23-L1 complex, highlighting a robust interaction between L1 and the target enzyme, with Tyr100 being one of the amino acids showing the highest frequency of interaction throughout the simulation. Density functional theory (DFT) analysis using the Becke, three-parameter, Lee-Yang-Parr (B3LYP)/6-31++G(d,p) basis set indicated a promising reactivity profile for the ligands. The analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties suggested that all inhibitor ligands possess favorable pharmacological characteristics, including appropriate molecular weight, lipophilicity, hydrogen bond donors and acceptors, molecular refractivity, topological polar surface area (TPSA), and the number of rotatable bonds, all in accordance with Ro5. Additionally, the physicochemical properties indicate that most ligands are capable of human intestinal absorption (HIA) and possess a wide therapeutic index, suggesting a favorable safety profile.

We synthesized a series of novel thiazoloquinolinone derivatives, achieving moderate to high yields ranging from 74 to 96%, and assessed their efficacy against Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) using in silico methodologies. The structures of these compounds were characterized through various spectroscopic techniques, including 1H-NMR, 13C-NMR, IR, and mass spectrometry. Comprehensive computational analyses, encompassing molecular docking, molecular dynamics (MD) simulations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, were conducted. Docking studies with VEGFR-2 revealed that all synthesized compounds exhibited docking scores between − 3.24 and − 6.63, indicating varying degrees of binding affinity. Notably, compound (5e) demonstrated the strongest binding affinity with an energy of − 6.63 kcal/mol. The MD simulations indicated that Lys868 was one of the amino acids exhibiting the highest frequency of interaction throughout the simulation. Analysis of the ADMET and physicochemical properties revealed that all inhibitor compounds possess favorable pharmacological characteristics.

Synthesized quinazolin-12-one derivatives as PDK1 inhibitors.

The epidermal growth factor receptor (EGFR), a protein located on the cell surface, belongs to the tyrosine kinase family and plays a crucial role in cell development and proliferation. Abnormal expression or mutations in the EGFR gene can lead to non–small cell lung cancer. Although established EGFR inhibitors have been effective in the treatment of cancer, they are associated with several side effects. As a result, there is an urgent need to develop novel EGFR inhibitors that can effectively target the receptor while causing no adverse side effects. In this study, a series of bis(6‐amino‐1,3‐dimethylpyrimidine‐2,4(1 H ,3 H )‐dione derivatives was synthesized in water at room temperature without the use of any catalyst, and pharmaceutical properties are investigated. Computational methods, including density functional theory (DFT), molecular docking, and molecular dynamics (MD), were utilized to investigate the chemical properties, drug‐like characteristics, and anticancer potential of the molecule. Quantum chemical calculations indicated that the molecules are relatively stable and exhibit significant electrophilic properties. The analysis of HOMO‐LUMO contour maps was conducted to illustrate charge density distributions that may be associated with biological activity. Docking studies with EGFR enzymes indicated that all compounds demonstrated favorable binding affinities, with docking scores ranging from −4.412 to −6.158 kcal/mol. Particularly, Compound 3f, with an energy of −6.158 kcal/mol, showed the best binding affinity, outperforming the native ligand, which had a docking score of −5.076 kcal/mol. The stability of the EGFR‐3f complex is significantly enhanced by the formation of five conventional hydrogen bonds and one carbon–hydrogen bond in ligand–protein interactions. MD simulations, which included analyses such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), molecular surface area (MolSA), and polar surface area (PSA), were conducted on the EGFR‐3f complex. It was found that the EGFR‐3f complex is stable, and the results show that Compound 3f has a strong interaction with the target enzyme.

Alzheimer’s disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between − 6.096 and − 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.

There are numerous uses for the pharmacological effects of thiazolo-pyridine and its derivatives. The main objective of the study was to synthesis 10 novel derivatives of thiazolo[3,2-a] pyridine-6,8-dicarbonitrile with a 22–78% yield, with a focus on their potential anti-diabetic properties. We investigated the interactions between these compounds and the enzyme α-amylase through an in silico study involving molecular docking. According to the docking analysis results, the resulting compounds had advantageous inhibitory properties. With a docking score of -7.43 kcal/mol against the target protein, compound 4e performed best. The stability root-mean-square deviation (RMSD) showed that the complex stabilizes after 25 ns and with minor perturbation at 80. The RMSF values of the ligand-protein complex indicate that the following residues have interacted with compound 4e during the MD simulation: Trp58, Trp59, Tyr62, Gln63, His101, Val107, lle148, Asn152, Leu162, Thr163, Gly164, Leu165, Asp197, Ala198, Asp 236, Leu237, His299, Asp300, and His305. Moreover, the pharmacokinetic and drug-like properties of the synthesized derivatives of 2-arylamino-dihydroindeno[1,2-b] pyrrol-4(1H)-one suggest that they have the potential to be effective inhibitors of α-amylase and should be considered for further research. Nevertheless, it is crucial to ascertain the in vivo and in vitro effectiveness of these compounds through biochemical and structural investigations.

Introduction: Multiple sclerosis (MS) is an autoimmune and inflammatory disease that destroys the protective coating of central nervous system (CNS) nerve fibers and affects over 2.8 million people worldwide. Despite several studies on new therapeutic targets and lead compounds, MS disease has limited treatment options. This condition may be caused by a complicated interaction of environmental and genetic variables. Studies showed that MS-associated microglial cells’ increased MAPK^ERK activity may cause CNS inflammation and oligodendrocyte damage. Thus, screening for lead compounds that inhibit MAPK^ERK may protect brain cells and slow disease progression.Methods: The study aims to discover compounds that may inhibit MAPK^ERK as a novel approach for protecting the nervous system in managing MS. The study includes in silico methods, such as virtual screening, molecular docking, Density-functional theory (DFT) investigations (using the B3LYP/6–31++G(d,p) basis set in a gas phase environment), drug likeness scores, and molecular dynamic (MD) simulations.Results and Discussion:During the docking process with the MAPK^ERK protein, it was shown that the ligand L₁₂ receptor had the best binding affinity, with a docking score of -6.18 kcal/mol. To investigate the stability of the binding, a 100 ns MD simulation was performed on the complex formed by the MAPK^ERK protein and L₁₂. The receptor-ligand combination exhibited significant stability throughout the duration of the MD simulation. Additionally, the pharmacokinetic and drug-likeness properties of these ligands suggest that they have the potential to be considered viable candidates for future development in MS management.