Molecular Docking Simulation Studies Research Articles

3D-QSAR, design, molecular docking and dynamics simulation studies of novel 6-hydroxybenzothiazole-2-carboxamides as potentially potent and selective monoamine oxidase B inhibitors

Background6-hydroxybenzothiazole-2-carboxamide is a novel, potent and specific inhibitor of monoamine oxidase B (MAO-B), which can be used to study the molecular structure and develop new neuroprotective strategies.ObjectiveThe aim of this study was to create an effective predictive model from 6-hydroxybenzothiazole-2-carboxamide derivatives to provide a reliable predictive basis for the development of neuroprotective MAO-B inhibitors for the treatment of neurodegenerative diseases.MethodsFirst, the compounds were constructed and optimized using ChemDraw and Sybyl-X software. Subsequently, QSAR modeling was performed using the COMSIA method in Sybyl-X to predict the IC50 values of a set of novel 6-hydroxybenzothiazole-2-carboxamide derivatives. The ten most promising compounds were screened based on the IC50 values and tested for molecular docking. Finally, the binding stability and dynamic behavior of these compounds with MAO-B receptors were analyzed by molecular dynamics simulation (MD).ResultsThe 3D-QSAR model showed good predictive ability, with a q2 value of 0.569, r2 value of 0.915, SEE of 0.109 and F value of 52.714 for the COMSIA model. Based on the model, we designed a series of novel 6-HBC derivatives and predicted their IC50 values by the QSAR model. Among them, compound 31.j3 exhibited the highest predicted IC50 value and obtained the highest score in the molecular docking test. MD simulation results showed that compound 31.j3 was stable in binding to the MAO-B receptor, and the RMSD values fluctuated between 1.0 and 2.0 Å, indicating its conformational stability. In addition, energy decomposition analysis revealed the contribution of key amino acid residues to the binding energy, especially Van der Waals interactions and electrostatic interactions play an important role in stabilizing the complex.ConclusionIn this study, the potential of 6-hydroxybenzothiazole-2-carboxamide derivatives as MAO-B inhibitors was systematically investigated by 3D-QSAR, molecular docking and MD simulations. The successfully designed compound 31.j3 not only demonstrated efficient inhibitory activity, but also verified its stable binding to MAO-B receptor by MD simulation, which provides strong support for the development of novel therapeutic drugs for neurodegenerative diseases. These findings provide important theoretical basis and practical guidance for future drug design and experimental validation.

Design, Synthesis and in Silico Molecular Docking Studies of Adamantanyl hydrazinylthiazoles as Potential Anti-diabetic Agents.

Diabetes mellitus is a widespread disease that poses a major threat to millions of people. To address this issue, we have synthesized seventeen new 4-(adamantan-1-yl)-(2-(arylidene)hydrazinyl)thiazolesvia Hantzsch synthetic approach. The molecular structures of all the compounds were confirmed using spectroscopic techniques. Protein kinase, α-amylase, glycation, and oxidation inhibition potential of all compounds were also investigated and it was found, compounds 3b, 3c, 3e-3g and 3i-3q have shown excellent α-amylase inhibition (IC50= 7.91 ± 0.07 to 28.57 ± 0.1 µM), compounds 3c, 3e, 3i, 3k and 3p (IC50= 30.6 ± 0.06 to 37.8 ± 0.005 ppm) were found to be highly potent anti-glycating agents and compounds 3c, 3g, 3h, 3k, and 3m were found more potent protein kinase inhibitors. The compounds 3b, 3c, 3d, 3e, 3f, 3g, 3i, 3k, 3l, 3m, 3n, 3p and 3q have shown good antioxidant potential (IC50= 27.5 ± 0.09 to 48.8 ± 0.09 µM). The biocompatibility of all samples was also tested by employing brine-shrimp lethality and in-vitro hemolytic assays and was found to be safe to human erythrocytes at tested concentrations. Furthermore, the Molecular docking simulation study also revealed that almost all synthesized compounds have potential interactions with target proteins at the molecular level.

Identification of Novel Progesterone Receptor (PR) Inhibitors (Homo sapiens) from Metabolites of Biotransformation Fungal: A Bioinformatics Approach

Background/Objectives: Steroids have demonstrated selective cytotoxic properties against tumor cells. The pro-gesterone receptor (PR) plays a vital role in the proliferation, cell differentiation, and maintenance of female reproductive tissue, and its malfunction can lead to breast cancer. The use of the biocatalytic method by filamentous fungi has sparked interest in the obtained of steroids due to the advantages of the process. Methods: Pharmacokinetic and toxicological properties (rat and mouse), molecular docking simulation studies, and prediction of the spectrum of biological activity were performed to select molecules with the potential for PR inhibition, from 155 biotransformed products of the progesterone. Subsequently, the chemical structures were subjected to an evaluation of their pharmacokinetic and toxicological properties and, with the application of ADMET filters. Results: Androstenedione, 17α-hydroxyprogesterone, and dihydrotestosterone, obtained by the process of biotransformation of PR by different filamentous fungi, showed good pharmacokinetic profiles and low toxicity compared to the control groups. The in-silico data associated with molecular docking studies revealed the best binding affinity and similarity in the interactions of these molecules against the human progesterone receptor target. Thus, the results of biological activity spectrum prediction highlight the great potential to investigate the role of molecular descriptors in the attribution of anti-cancer activities. Conclusions: The biocatalytic process, by filamentous fungi, can provide important molecules as a product of progesterone biotransformation, such as androstenedione, 17α-hydroxyprogesterone, and dihydrotestosterone. In this study we showed that these molecules have good pharmacokinetic profiles and low toxicity for antineoplastic activity (breast cancer).

Assessing the efficacy of iso-mukaadial acetate and betulinic acid against selected Plasmodium falciparum glycolytic pathway proteins: in silico and in vitro studies

Malaria is the extensive health concern in sub-Saharan Africa, with Plasmodium falciparum being the most lethal strain. The continued emergence of drug-resistant P. falciparum advocates for the development of new antimalarials. Our current study aimed to effectively explore the interaction capabilities of iso-mukaadial acetate (IMA) and betulinic acid (BA) against two essential P. falciparum glycolytic pathway proteins, PfLDH and PfHk. Recombinant PfLDH and PfHk were independently expressed in E. coli BL21 (DE3) cells and subsequently purified using affinity chromatography. Protein–ligand interaction studies probed in silico and in vitro approaches. Parasite inhibition studies confirmed potent antimalarial activity against the P. falciparum NF54 strains, with BA and IMA showing IC50 values of 1.27 µg/ml and 1.03 µg/ml against the asexual stage of P. falciparum, respectively. FTIR experiments confirmed interactions between the compounds and the secondary structure of the proteins. Direct protein–ligand interaction studies analysis using microscale thermophoresis (MST) showed a KD value of 0.1036 ± 0.6001 µM for the PfLDH-BA complex and 0.7473 ± 0.3554 µM KD value for PfLDH-IMA. Meanwhile, PfHk-IMA had 0.39701 ± 0.16298 µM KD value, while the PfHk-BA complex had no interaction detected. Molecular docking and molecular dynamics simulation studies were used to measure and confirm the interactive strength of complexes. Molecular docking reported a binding score of − 1.155 kcal/mol for the PfLDH-BA complex and a binding score of − 3.200 kcal/mol for PfLDH-IMA. The PfHk-BA complex had − 2.871 kcal/mol and PfHk-IMA complex had − 4.225 kcal/mol binding score. In conclusion, BA and IMA compounds had better interactions and remained bound within the binding sites of the glycolytic pathway proteins (PfLDH and PfHk).

Biological Effects of Calceolarioside A as a Natural Compound: Anti-Ovarian Cancer, Anti-Tyrosinase, and Anti-HMG-CoA Reductase Potentials with Molecular Docking and Dynamics Simulation Studies.

One kind of hydroxycinnamic acid is calceolarioside A. Plantago coronopus, Cassinopsis madagascariensis, and other organisms for whom data are available are known to have this naturally occurring compound. IC50 values of Calceolarioside A for ovarian cell lines (NIH-OVCAR-3, ES-2, UACC-1598, Hs832.Tc, TOV-21G, UWB1.289) were 24.42, 13.50, 9.31, 14.90, 20.07, and 16.18µM, respectively. IC50 values were 19.83 and 73.48µM for tyrosinase and HMG-CoA reductase enzymes. The chemical activities of Calceolarioside A against HMG-CoA reductase and tyrosinase were assessed by conducting the molecular docking study, MM/GBSA calculation, and molecular dynamics (MD) simulation. The anticancer activities of this compound were evaluated against some ovarian cancer cells, such as NIH-OVCAR-3, ES-2, UACC-1598, Hs832.Tc, TOV-21G, and UWB1.289 cell lines. The chemical activities of Calceolarioside A against some of the expressed surface receptor proteins (folate receptor, CD44, EGFR, Formyl Peptide Receptor-Like 1, M2 muscarinic receptor, and estrogen receptors) were investigated using computational methods. The results exhibited the interplay among atoms. The compound formed robust associations with both the enzymes and receptors. Calceolarioside A can hinder the functioning of these enzymes and the proliferation of malignant cells.

Investigating the Inhibitory Mechanism of para-Sulfonato-calix[4]arenes against Polymerase and Helicase of SARS-CoV-2: Molecular Docking and Dynamics Simulation Studies

The coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound impact on global health and socio-economic conditions. To date, various vaccines have been administered worldwide in an effort to curb the spread of the virus. Despite vaccination efforts, there have been complications. Existing antiviral drugs have shown limited effectiveness, prompting the use of computational methods to understand the dynamics of the virus and develop suitable treatments. The current study focuses on using biocompatible para-sulfonato-calix[4]arenes to dock against two key proteins of SARS-CoV-2, namely ribonucleic acid (RNA)-dependent RNA polymerase, and helicase. Docking results indicate a strong binding affinity of these compounds to the target proteins, with higher scores compared to commonly used medications. Molecular dynamics (MD) simulation validates the docking results, showing stable protein-ligand complexes over time. The compounds are also screened for absorption, distribution, metabolism, and excretion properties and toxicity, suggesting their potential as lead candidates for inhibiting the virus’s key proteins. However, further in vivo and in vitro studies are recommended to confirm these findings.

Deciphering the role of flutamide, fluorouracil, and furomollugin based ionic liquids in potent anticancer agents: Quantum chemical, medicinal, molecular docking and MD simulation studies

Deciphering the role of flutamide, fluorouracil, and furomollugin based ionic liquids in potent anticancer agents: Quantum chemical, medicinal, molecular docking and MD simulation studies

Novel desfluoroquinolone–sulfonamide hybrids as potential anti-MRSA agents: synthesis, drug-likeness, molecular docking, and molecular dynamics simulation study

A molecular hybridization strategy was used to combine quinolone and sulfonamide structures to synthesize 16 quinolone–sulfonamide hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus.

Inhibition of monoamine oxidases by heterocyclic derived conjugated dienones: synthesis and in vitro and in silico investigations.

A total of 18 heterocyclic derived conjugated dienones (CD1-CD18) were evaluated for their potential monoamine oxidase (MAO)-A/-B inhibitory activity. Among the analyzed molecules, CD11 and CD14 showed notable inhibitory potentials against MAO-B, with half-maximal inhibitory concentration (IC50) values of 0.063 ± 0.001 μM and 0.036 ± 0.008 μM, respectively. In contrast, CD1, CD2 and CD3 showed comparable inhibitory activities toward MAO-A, with IC50 values of 3.45 ± 0.07, 3.23 ± 0.24, and 3.15 ± 0.10 μM, respectively. Derivatives of thiophene (CD13-CD17) exhibited selectivity indices greater than 250 for MAO-B. Both lead compounds exhibited similar potencies to safinamide and were more potent than pargyline. According to kinetic analysis, CD11 and CD14 exhibited competitive inhibition of MAO-B activity, with K i values of 12.67 ± 3.85 nM and 4.5 ± 0.62 nM, respectively. Furthermore, the reversibility test results indicated that the inhibitions were reversible. Molecular docking and molecular dynamics simulation studies can provide insights into the probable binding interactions of CD11 and CD14 with MAO-B. CD11 demonstrated a bipartite contact with Tyr326 and Phe343, whereas CD14 showed contact with Pro102 and Tyr435 via aromatic hydrogen bonds. These results indicated that both compounds have high-affinity binding interactions ( -10.13 and -9.90 kcal mol-1, respectively) at the active site of MAO-B. Furthermore, we used SwissADME to estimate ADME, and both lead compounds demonstrated blood-brain barrier penetration. The study results indicated that all the compounds evaluated demonstrated potent inhibition of MAO-B activity, which was comparable to the efficacy of reference medications. It is necessary to do further investigations on the lead molecules to see whether they may be used to treat different neurodegenerative illnesses.

Vitamin B6 Via p-JNK/Nrf-2/NF-κB Signaling Ameliorates Cadmium Chloride-Induced Oxidative Stress Mediated Memory Deficits in Mice Hippocampus.

Cadmium chloride (Cd) is a pervasive environmental heavy metal pollutant linked to mitochondrial dysfunction, memory loss, and genetic disorders, particularly in the context of neurodegenerative diseases like Alzheimer's disease (AD). This study investigated the neurotherapeutic potential of vitamin B6 (Vit. B6) in mitigating Cd-induced oxidative stress and neuroinflammation-mediated synaptic and memory dysfunction. Adult albino mice were divided into four groups: Control (saline-treated), Cd-treated, Cd+Vit. B6- treated, and Vit. B6 alone-treated. Cd and Vit. B6 were administered intraperitoneally, and behavioral tests (Morris Water Maze, Y-Maze) were conducted. Subsequently, western blotting, antioxidant assays, blood glucose, and hyperlipidemia assessments were performed. Cd-treated mice exhibited impaired cognitive function, while Cd+Vit. B6-treated mice showed significant improvement. Cd-induced neurotoxic effects, including oxidative stress and neuroinflammation, were observed, along with disruptions in synaptic proteins (SYP and PSD95) and activation of p-JNK. Vit. B6 administration mitigated these effects, restoring synaptic and memory deficits. Molecular docking and MD simulation studies confirmed Vit. B6's inhibitory effect on IL-1β, NRF2, and p-JNK proteins. These results highlight Vit. B6 as a safe therapeutic supplement to mitigate neurodegenerative disorders, emphasizing the importance of assessing nutritional interventions for combating environmental neurotoxicity in the interest of public health.

Histone deacetylase 8 in focus: Decoding structural prerequisites for innovative epigenetic intervention beyond hydroxamates

Histone deacetylase 8 (HDAC8) inhibitors play a pivotal role in epigenetic regulation. Numerous HDAC8 inhibitors (HDAC8is), that are non-hydroxamates have been identified to date, and a few of them exhibit antiproliferative activity that is on par with hydroxamates. While many non-hydroxamate-based HDAC8is have demonstrated selectivity, hydroxamate-based HDAC8is, like Vorinostat and TSA, have a tendency of non-specificity among the different HDAC isoforms. Moreover, because of the unfavorable toxic side effects, there are significant concerns surrounding the use of hydroxamate derivatives as therapeutic agents in cancer as well as other chronic diseases. Consequently, the research on non-hydroxamate-based HDAC8is is of utmost priority. In the present study, a comprehensive study was presented to unravel the structural requirements for non-hydroxamate-based HDAC8is from a diverse set of 866 compounds. The study utilized Classification-based Quantitative Structure-Activity Relationship (QSAR) analysis, incorporating Bayesian classification, Recursive partitioning, and other machine learning methods to pinpoint the key structural features essential for HDAC8 inhibition. To underscore and gain deeper insights into the identified structural features, molecular docking, and molecular dynamic (MD) simulation studies were conducted. The integration of these computational approaches unveiled key structural motifs essential for potent HDAC8 inhibitory activity, shedding light on the molecular basis of HDAC8 inhibition using non-hydroxamates.

Molecular docking and molecular dynamics simulation studies of inhibitor candidates against Anopheles gambiae 3-hydroxykynurenine transaminase and implications on vector control.

Isoxazole and oxadiazole derivatives inhibiting 3-hydroxykynurenine transaminase (3HKT) are potential larvicidal candidates. This study aims to identify more suited potential inhibitors of Anopheles gambiae 3HKT (Ag3HKT) through molecular docking and molecular dynamics simulation. A total of 958 compounds were docked against Anopheles gambiae 3HKT (PDB ID: 2CH2) using Autodock vina and Autodock4. The top three identified hits were subjected to 300 ns molecular dynamics simulation using AMBER 18 and ADMET analysis using SWISSADME predictor and ADMETSAR. Replacement of alkyl attachment on C5 of isoxazole or oxadiazole derivative with a cycloalkyl group yielded compounds with lower binding energy than their straight chain counterparts. The top three compounds were brominated compounds, 2-[3-(4-bromophenyl)-1,2-oxazol-5-yl]cyclopentane-1-carboxylic acid, 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxylic acid, 3-[3-(4-bromo-2-methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxylic acid, and they had binding energies of -8.58, -8.25, and -8.18kcal/mol in virtual screening against 2CH2 protein target, respectively. These compounds were predicted to be less toxic than temephos, a standard larvicide and more biodegradable than previously reported inhibitors. The three compounds exhibited a greater stabilizing effect on 2CH2 protein target than 4-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]butanoic acid, a previously reported inhibitor candidate with good larvicidal activity on Aedes aegypti. Further thermodynamic calculations revealed that the top three compounds possessed total binding energies (ΔGbind) of -26.64kcal/mol, -24.26kcal/mol and -14.11kcal/mol, respectively, as compared to -12.02kcal/mol for 4-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]butanoic acid. These compounds could be better larvicides than previously reported isoxazole or oxadiazole derivatives and safer than temephos.

Molecular Characterization and Potential Inhibitors Prediction of Protein Arginine Methyltransferase-2 in Carcinoma: An Insight from Molecular Docking, ADMET Profiling and Molecular Dynamics Simulation Studies.

To predict and characterize the three-dimensional (3D) structure of protein arginine methyltransferase 2 (PRMT2) using homology modeling, besides, the identification of potent inhibitors for enhanced comprehension of the biological function of this protein arginine methyltransferase (PRMT) family protein in carcinogenesis. An in silico method was employed to predict and characterize the three-dimensional structure. The bulk of PRMTs in the PDB shares just a structurally conserved catalytic core domain. Consequently, it was determined that ligand compounds may be the source of co-crystallized complexes containing additional PRMTs. Possible PRMT2 inhibitor compounds are found by using S-adenosyl methionine (SAM), a methyl group donor, as a positive control. Protein arginine methyltransferases are associated with a range of physiological processes, including as splicing, proliferation, regulation of the cell cycle, differentiation, and signaling of DNA damage. These functional capacities are also related to carcinogenesis and metastasis-several forms of PRMT have been cited in the literature. These include PRMT-1, PRMT-2, and PRMT-5. Among these, the role of PRMT-2 has been shown in breast cancer and hepatocellular carcinoma. To gain more insights into the role of PRMT2 in cancer pathogenesis, we opted to characterize tertiary structure utilizing an in silico approach. The majority of PRMTs in the PDB have a structurally conserved catalytic core domain. Thus, ligand compounds were identified as a possible source of co-crystallized complexes of other PRMTs. The SAM, a methyl group donor, is used as a positive control in order to identify potential inhibitor compounds of PRMT2 by the virtual screening method. We hypothesized that an inhibitor for other PRMTs could alter PRMT2 activities. Out of 45 inhibitor compounds, we ultimately identified three potential inhibitor compounds based on the results of the pharmacokinetics and binding affinity studies. These compounds are identified as 3BQ (PubChem CID: 77620540), 6DX (PubChem CID: 124222721), and TDU (PubChem CID: 53346504). Their binding affinities are -8.5 kcal/mol, -8.1 kcal/mol, and -8.8 kcal/mol, respectively. These compounds will be further investigated to determine the binding stability and compactness using molecular dynamics simulations on a 100 ns time scale. In vitro and in vivo studies may be conducted with these three compounds, and we think that focusing on them might lead to the creation of a PRMT2 inhibitor. Three strong inhibitory compounds that were non-carcinogenic also have drug-like properties. By using desirable parameters in root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), molecular surface area (MolSA), and intermolecular hydrogen bonding, complexes verified structural stability and compactness over the 100 ns time frame. Hossen MS, Islam MN, Pramanik MEA et al. Molecular Characterization and Potential Inhibitors Prediction of Protein Arginine Methyltransferase-2 (PRMT2) in Carcinoma: An Insight from Molecular Docking, ADMET Profiling and Molecular Dynamics Simulation Studies. Euroasian J Hepato-Gastroenterol 2024;14(2):160-171.

Multi-Target Quinoxaline Derivatives for Alzheimer’s Disease: Inhibitory Activities Against AChE and BACE-1 Enzymes

New choline esterase inhibitors and B-secretase inhibitors present promising treatment options for the treatment of Alzheimer's disease (AD). In this study, molecular docking was performed using our chemistry library to discover lead compounds. Molecular docking was employed to predict binding affinities, while molecular dynamics (MD) simulations provided insights into the stability of the ligand–enzyme interactions. To improve the activity, 12 new derivatives were designed and synthesized based on the lead compound obtained. The structures of the synthesized compounds were identified by 1H-NMR,13C-NMR, and HRMS techniques. Their activities on choline esterase enzymes and Beta-secretase 1 enzyme were elucidated through in vitro studies. Compound 4f had an IC50 = 0.026 ± 0.001 µ. value against the acetylcholinesterase (AChE) enzyme and an IC50 = 0.125 ± 0.005 µ. value against the BACE-1 enzyme. The excellent activity of compound 4f was supported by molecular docking and MD simulation studies.

Small Molecule with Big Impact: Metarrestin Targets the Perinucleolar Compartment in Cancer Metastasis.

Metarrestin (ML246) is a first-in-class pyrrole-pyrimidine-derived small molecule that selectively targets the perinucleolar compartment (PNC). PNC is a distinct subnuclear structure predominantly found in solid tumor cells. The occurrence of PNC demonstrates a positive correlation with malignancy, serving as an indicator of tumor aggressiveness, progression, and metastasis. Various promising preclinical results have led to the clinical translation of metarrestin into a first-in-human trial. This review aims to summarize (i) the current understanding of the structure and function of PNC and its role in cancer progression and metastasis, (ii) key findings from studies examining the effect of metarrestin on various cancers across the translational spectrum, including in vitro, in vivo, and human clinical trial studies, and (iii) the pharmaceutical relevance of metarrestin as a promising anticancer candidate. Furthermore, our molecular docking and MD simulation studies show that metarrestin binds to eEF1A1 and eEF1A2 with a strong and stable affinity and inhibits eEF1A2 more efficiently compared to eEF1A1. The promising results from preclinical studies suggest that metarrestin has the potential to revolutionize the treatment of cancer, heralding a paradigm shift in its therapeutic management.

Synthesis, exploring the structural, non covalent interaction effects, biological assessment, molecular docking and quantum chemical properties of functionalized new N-nitrosopiperidin-4-one: An experimental and theoretical study

The synthesis of 3-benzyl-1-nitroso-2,6-di-p-tolylpiperidin-4-one 2 has been carried via the nitrosation of 3-benzyl-2,6-di-p-tolylpiperidin-4-one 1 with sodium nitrite and dilute hydrochloric acid at room temperature. This work deals with the synthesis, characterization (1H and 13C NMR, 1H–1H-COSY, 1H–13C-COSY, and X-ray diffraction analysis), and stereochemical characterization of functionalized N-nitrosopiperidin-4-one. The molecular level behaviors of the compounds were determined by computational chemistry methods. It is to be noted that at room temperature, 3-benzyl-2,6-di-p-tolylpiperidin-4-one 1 preferentially exists in chair conformation with all substituents in equatorial orientation, whereas its nitroso derivative, 3-benzyl-1-nitroso-2,6-di-p-tolylpiperidin-4-one 2, exists in syn and anti isomers. The observed coupling constant data for 2 suggests that the syn isomer is an equilibrium mixture of two boat forms B1 and B2, and that the predominant conformer of the anti-isomer is boat form B1. Conformational analysis carried out through DFT calculation using Gaussian 09 program supported that B1 is the more stable conformer of compound 2 with minimum energy for both syn and anti isomers. Good correlations were obtained between the predicted boat conformation B1 from theoretical study (DFT calculation) and the corresponding experimental (1H NMR spectrum) ones. This was complemented by single-crystal X-ray analysis, which revealed that compound 2 exists as the anti-isomer with the piperidine ring adopting the B1 boat structure. Here, the phenyl group at C(2) and the benzyl group at C(3) are in axial orientation, and the phenyl group at C(6) are in equatorial orientation. Hirshfeld surface analysis of the molecule showed H⋯H (59.0 %), C⋯H/H⋯C (22.9 %), O⋯H/H⋯O (14.3 %), N⋯H/H⋯N (2.4 %), and O⋯O (0.5 %) interactions. Energy framework analysis revealed that among the components of the framework energies, electrostatic repulsion (Erep) is dominant. Finally, the molecular docking and dynamics simulation studies of the title ligand with 6LVM protein have shown better binding affinity, and stability. Further, ADME prediction of the compound 2 has exhibited excellent drug-likeness.

Exploring potential GPR55 agonists using virtual screening, molecular docking and dynamics simulation studies

GPR55, an orphan GPCR, holds significance in the context of neurological disorders and its activation is important for regulating neurological responses. This has led us to uncover and explore a set of ligands which may act as potential agonists. We have predicted the GPR55 structural model followed by molecular docking, dynamics simulation studies, free energy landscape and MMPBSA analyses to study the dynamic nature of GPR55 in the presence of different ligands. We initially carried out structure-based virtual screening of a dataset from ChemDiv Database against the GPR55 model. Based on the docking results, it was observed that thiazole and triazole derivatives were present among the top hits and notably, two compounds – one thiazole (lead1) and one triazole (lead2) derivative were shortlisted. In addition, as we are working on the design, synthesis, structural and functional properties of several thiazole and triazole compounds, we have attempted to study the binding potential of two compounds SVS1 (thiazole derivative) and SVS2 (triazole derivative) with GPR55. The synthesis and structural aspects of SVS1 and SVS2 were previously reported by our team. Further, we have included a known agonist O-1602 in the present study for comparative analysis. All the compounds showed promising interactions with GPR55 during molecular dynamics simulations. Our findings suggest that lead1, lead2, SVS1 and SVS2 have the potential to serve as GPR55 agonists and the study throws light on the importance of thiazole and triazole moieties in the ligands. This offers a promising avenue for the development of new therapies for neurological disorders.

Discovery of novel CDK2 inhibitors for cancer treatment: integrating ligand-based pharmacophore modelling, molecular docking, DFT, ADMET, and molecular dynamics simulation studies

BackgroundThe global landscape of public health faces significant challenges attributed to the prevalence of cancer and the emergence of treatment resistance. This study addresses these challenges by focusing on Cyclin-dependent Kinase 2 (CDK2) and employing a systematic computational approach for the discovery of novel cancer therapeutics.ResultsInitial ligand-based pharmacophore modelling, utilizing a training set of five reported CDK2 inhibitors, yielded a robust model characterized by Aro|Hyd| and |Acc|Don| features. Screening this validated model against the ZINC database identified 1881 hits, which were further subjected to molecular docking studies. The top 10 compounds (Z1–Z10) selected from the docking studies underwent Pharmacokinetic parameters Absorption, Distribution, Metabolism, Excretion and Toxicity profiling, Density Functional Theory (DFT) studies and the top two went for 100ns molecular dynamics (MD) simulations by comparing them with the standard Roscovitine. Compounds Z1 and Z2 emerged as the most promising, with docking scores of − 8.05 kcal/mol and − 8.02 kcal/mol, respectively. DFT analysis of the top 10 compounds revealed minimal variations in highest occupied molecular orbital–lowest unoccupied molecular orbital energy gaps, indicating consistent electronic stability and reactivity across the candidates. MD simulations of Z1 and Z2 confirmed their stable interactions with CDK2, with root mean square deviation (RMSD) values ranging from 1.4 to 2.5 Å for Z1 and 1.5 to 2.4 Å for Z2.ConclusionThe current research identified compounds Z1 and Z2, which demonstrated significant potential as potent CDK2 inhibitors for cancer therapy, providing valuable insights into the development of more effective CDK2 inhibitors and addressing the critical need for innovative therapeutic strategies in cancer treatment.Graphical abstract

Quantum Mechanical Calculations and Molecular Docking Simulation Studies of N-(5-chloro-2-oxobenzyl)-2-hydroxy-5-methylanilinium Compound

Schiff bases were first synthesized by Hugo Schiff in 1864. The formation of a carbon-nitrogen double bond is what gives specificity to Schiff bases. This double bond is referred to as an imine (R-N=C-R). This double bond contributes to the high activity of Schiff bases, allowing for extensive research across various fields and disciplines. Neurodegenerative diseases are conditions that continuously and irreversibly affect neurons and nerve cells in the central nervous system, and they are among the leading causes of death in developed countries. Alzheimer’s disease, which is a type of neurodegenerative disease, currently has about 5 million new cases each year, and there is no definitive and complete treatment method for it. Individuals with this disease exhibit symptoms such as memory loss, inability to form new memories, and slowing of cognitive functions. Additionally, these patients show imbalances in neurotransmitters responsible for facilitating neural transmission between neurons, particularly an irreversible loss of cholinergic neurons, which are a significant part of the central nervous system. Disruption of homeostasis in the mechanisms of acetylcholinesterase (AChE) and monoamine oxidase (MAO) neurotransmitters is indicated among the causes of Alzheimer’s disease. In this study; the physical, chemical and biological properties of N-(5-chloro-2-oxobenzyl)-2-hydroxy-5-methylanilinium molecule were investigated by quantum mechanical calculation methods. In support of the X-ray results, the geometrical parameters (bond lengths, and bond angles) and quantum chemical properties of the title compound were theoretically realized by the density functional theory method with B3LYP/6-311G(d,p) basis set using Gaussian 03W program. Herein, Frontier orbitals, molecular electrostatic potential surface, nonlinear optical properties, natural bond orbital analysis, Mulliken charges, and Hirshfeld surface analysis of the title compound were also calculated to explain the intermolecular interactions. Additionally, molecular docking results were performed with AChE and MAO-B enzymes obtained from the Protein Data Bank (PDB). All these studies have shown that the structure has high stability and forms a strong bond with the relevant enzymes.

Computational analysis of molecular details on the interaction of C,N-cyclometalated 2H-indazole Ru(II) and Ir(III) complexes with cancer protein targets

A small library of different C,N-cyclometalated complexes of Ru(II) and Ir(III) with 2H-indazole ligand were investigated for their potential as inhibitors for protein targets that are known to play crucial roles in various cancer pathways. These targets play key roles in cell proliferation, apoptosis, cell migration, angiogenesis, inflammation, cell differentiation and in the activation of pro-inflammatory cytokines, etc. With experimental evidences available on the inhibition potential of these metal complexes, detailed molecular mechanisms of these metal complexes and their significant interactions that modulate the functions of cancer protein targets are not available and this forms the core of this investigation. Ten different protein targets were identified and the initial screening was done through molecular docking and the results have identified 4WOY, a receptor protein of Drp1 that plays crucial roles in mitochondrial fission process. Further investigations on the interaction of the proposed metal complexes as inhibitors for the above identified protein target were carried out through molecular docking and dynamic simulation studies. The possible interactions along with their energetics were analysed and discussed in detail.