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Background Alzheimer’s disease (AD) is a neurological condition that primarily affects older people. Currently available AD drugs are associated with side effects and there is a need to develop natural drugs from plants. Aquilaria is as an endangered medicinal plant genus (commonly called agarwood plants) and various products of Aquilaria plant spp. including resinous heartwood, leaves, bark, and stem have been widely used in various traditional medicine systems. Research on agarwood plants is sparse and only a few previous studies demonstrated their neuroprotective properties in vitro. Owing to the presence of a plethora of secondary metabolites in agarwood plants, it is imperative not only to protect these plants but also evaluate the bioactivity of agarwood phytochemicals. Methods This study used Molsoft tools to predict the physicochemical properties of agarwood ligands, including the number of H-bond donors and acceptors, polar surface area, lipophilicity, solubility, and the molecular polar surface area and volume of agarwood ligands. Additionally, ADMET (absorption, digestion, metabolism, excretion, and toxicity) properties were predicted using ADMETlab 2.0. Computational methods such as AutoDock Vina and molecular dynamic (MD) simulations were employed for the docking of 41 selected agarwood compounds with AD-related molecular targets. Results and Conclusion According to docking data, three compounds aquilarisin (ASN), aquilarisinin (ANN), aquilarixanthone (AXN) showed highest binding affinity to selected AD targets compared to their known inhibitors. MD simulation studies revealed that, selected agarwood compounds’ protein-ligand complexes showed remarkable structural stability throughout 100ns simulation. The agarwood chemicals aquilarisin, aquilarisinin, aquilarixanthone, pillion (PLN), and agarotetrol (AGT) are consequently suggested as some of the found hits against AD targets, however, additional experimental validation is required to establish their effectiveness.

Background Alzheimer’s disease (AD) is a neurological condition that primarily affects older people. Currently available AD drugs are associated with side effects and there is a need to develop natural drugs from plants. Aquilaria is as an endangered medicinal plant genus (commonly called agarwood plants) and various products of Aquilaria plant spp. including resinous heartwood, leaves, bark, and stem have been widely used in various traditional medicine systems. Research on agarwood plants is sparse and only a few previous studies demonstrated their neuroprotective properties in vitro. Owing to the presence of a plethora of secondary metabolites in agarwood plants, it is imperative not only to protect these plants but also evaluate the bioactivity of agarwood phytochemicals. Methods This study used Molsoft tools to predict the physicochemical properties of agarwood ligands, including the number of H-bond donors and acceptors, polar surface area, lipophilicity, solubility, and the molecular polar surface area and volume of agarwood ligands. Additionally, ADMET (absorption, digestion, metabolism, excretion, and toxicity) properties were predicted using ADMETlab 2.0. Computational methods such as AutoDock Vina and molecular dynamic (MD) simulations were employed for the docking of 41 selected agarwood compounds with AD-related molecular targets. Results and Conclusion According to docking data, three compounds aquilarisin (ASN), aquilarisinin (ANN), aquilarixanthone (AXN) showed highest binding affinity to selected AD targets compared to their known inhibitors. MD simulation studies revealed that, selected agarwood compounds’ protein-ligand complexes showed remarkable structural stability throughout 100ns simulation. The agarwood chemicals aquilarisin, aquilarisinin, aquilarixanthone, pillion (PLN), and agarotetrol (AGT) are consequently suggested as some of the found hits against AD targets, however, additional experimental validation is required to establish their effectiveness.

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Background and purpose: Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 25% of breast cancer patients; therefore, its inhibition is a therapeutic target in cancer treatment. Experimental approach: In this study, two new variants of designed ankyrin repeat proteins (DARPins), designated EG3-1 and EG3-2, were designed to increase their affinity for HER2 receptors. To this end, DARPin G3 was selected as a template, and six-point mutations comprising Q26E, I32V, T49A, L53H, K101R, and G124V were created on its structure. Furthermore, the 3D structures were formed through homology modeling and evaluated using molecular dynamic simulation. Then, both structures were docked to the HER2 receptor using the HADDOCK web tool, followed by 100 ns of molecular dynamics simulation for both DARPins / HER2 complexes. Findings/Results: The theoretical result confirmed both structures' stability. Molecular dynamics simulations reveal that the applied mutations on DARPin EG3-2 significantly improve the receptor binding affinity of DARPin. Conclusion and implications: The computationally engineered DARPin EG3-2 in this study could provide a hit compound for the design of promising anticancer agents targeting HER2 receptors.

Background Alzheimer's disease (AD) is a neurological condition that primarily affects older people. Currently available AD drugs are associated with side effects and there is a need to develop natural drugs from plants. Aquilaria is as an endangered medicinal plant genus (commonly called agarwood plants) and various products of Aquilaria plant spp. including resinous heartwood, leaves, bark, and stem have been widely used in various traditional medicine systems. Research on agarwood plants is sparse and only a few previous studies demonstrated their neuroprotective properties in vitro. Owing to the presence of a plethora of secondary metabolites in agarwood plants, it is imperative not only to protect these plants but also evaluate the bioactivity of agarwood phytochemicals. Methods Computational methods such as AutoDock Vina and molecular dynamic (MD) simulations were employed for the docking of 41 selected agarwood compounds with AD-related molecular targets. Results and Conclusion According to docking data, three compounds aquilarisin, aquilarisinin, aquilarixanthone showed highest binding affinity to selected AD targets compared to their known inhibitors. MD simulation studies revealed that, selected agarwood compounds' protein-ligand complexes showed remarkable structural stability throughout 100 ns simulation. The agarwood chemicals aquilarisin, aquilarisinin, aquilarixanthone, pillion, and agarotetrol are consequently suggested as some of the found hits against AD targets, however, additional experimental validation is required to establish their effectiveness.

Aims: The machine learning-based QSAR modeling procedure, molecular generations, and molecular dynamic simulations were applied to virtually screen the DNA polymerase theta inhibitors., Background: The DNA polymerase theta (Polθ or POLQ) is an attractive target for treatments of homologous recombination deficient (such as BRCA deficient) cancers. There are no approved drugs for targeting POLQ, and only one inhibitor is in Phase Ⅱclinical trials; thus, it is necessary to develop novel POLQ inhibitors., Objectives: To build machine learning models that predict the bioactivities of POLQ inhibitors. To build molecular generation models that generate diverse molecules. To virtually screen the generated molecules by the machine learning models. To analyze the binding modes of the screening results by molecular dynamic simulations., Methods: In the present work, 325 inhibitors with POLQ polymerase domain bioactivities were Collected. Two machine learning methods, random forest and deep neural network, were used for building the ligand- and structure-based quantitative structure-activity relationship (QSAR) models. The substructure replacement-based method and transfer learning-based deep recurrent neural network method were used for molecular generations. Molecular docking and consensus QSAR models were carried out for virtual screening. The molecular dynamic simulations and MM/GBSA binding free energy calculation and decomposition were used to further analyze the screening results., Results: The MCC values of the best ligand- and structure-based consensus QSAR models reached 0.651 and 0.361 for the test set, respectively. The machine learning-based docking scores had better-predicted ability to distinguish the highly and weakly active poses than the original docking scores. The 96490 molecules were generated by both molecular generation methods, and 10 molecules were retained by virtual screening. Four favorable interactions were concluded by molecular dynamic simulations., Conclusion: We hope that the screening results and the binding modes are helpful for designing the highly active POLQ polymerase inhibitors and the models of the molecular design workflow can be used as reliable tools for drug design., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively., Methods: We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β., Results: Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies., Conclusion: Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Stenotrophomonas maltophilia is a multi-drug resistant, gram-negative bacterium that causes opportunistic infections and is associated with high morbidity and mortality in severely immunocompromised individuals., Aim: The study aimed to find out the drug target and a novel inhibitor for Stenotrophomonas maltophilia., Objectives: The current study focused on identifying specific drug targets by subtractive genomes analysis to determine the novel inhibitor for the specified target protein by virtual screening, molecular docking, and molecular simulation approach., Materials and Methods: In this study, we performed a subtractive genomics approach to identify the novel drug target for S.maltophilia. After obtaining the specific target, the next step was to identify inhibitors that include calculating 2D similarity search, molecular docking, and molecular simulation for drug development for S.maltophilia., Results: With an efficient subtractive genomic approach, out of 4386 proteins, five unique targets were found, in which UDP-D-acetylmuramic (murF) was the most remarkable target. Further virtual screening, docking, and dynamics analyses resulted in the identification of seven novel inhibitors., Conclusion: Further, in vitro and in vivo bioassay of the identified novel inhibitors could facilitate effective drug use against S.maltophilia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: SARS-CoV-2, which emerged in Wuhan, China, is a new global threat that has killed millions of people and continues to do so. This pandemic has not only threatened human life but has also triggered economic downturns across the world. Researchers have made significant strides in discovering molecular insights into SARSCoV- 2 pathogenesis and developing vaccines, but there is still no successful cure for SARS-CoV-2 infected patients., Objective: The present study has proposed a drug-repositioning pipeline for the design and discovery of an effective fungal-derived bioactive metabolite as a drug candidate against SARS-CoV-2., Methods: Fungal derivative "Cordycepin" was selected for this study to investigate the inhibitory properties against RNA-dependent RNA polymerase (RdRp) (PDB ID: 6M71) of SARS-CoV-2. The pharmacological profile, intermolecular interactions, binding energy, and stability of the compound were determined utilizing cheminformatic approaches. Subsequently, molecular dynamic simulation was performed to better understand the binding mechanism of cordycepin to RdRp., Results: The pharmacological data and retrieved molecular dynamics simulations trajectories suggest excellent drug-likeliness and greater structural stability of cordycepin, while the catalytic residues (Asp760, Asp761), as well as other active site residues (Trp617, Asp618, Tyr619, Trp800, Glu811) of RdRp, showed better stability during the overall simulation span., Conclusion: Promising results of pharmacological investigation along with molecular simulations revealed that cordycepin exhibited strong inhibitory potential against SARSCoV- 2 polymerase enzyme (RdRp). Hence, cordycepin should be highly recommended to test in a laboratory to confirm its inhibitory potential against the SARS-CoV-2 polymerase enzyme (RdRp)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

CrMnFeCoNi high entropy alloys holding several principle elements have displayed exceptional strength, ductility and damage tolerance, and these properties are even better at cryogenic temperature. Among CrMnFeCoNi and its derivatives, NiCoCr, called medium entropy alloy (MEA), has shown the best mechanical properties. Yet, research on the welding of NiCoCr is still in its infancy, which, to certain extent, renders the application of such advanced alloys in engineering structures. Here, for the first time, laser welding is employed to join NiCoCr MEA to achieve butt-type joints; microstructure and mechanical properties at 300 K and 77 K are then examined by experiments and molecular dynamic (MD) simulation. It is found that the ultimate tensile strength (UTS) and ductility of the weld at 300 K are 525 ± 36 MPa and 85 ± 15%, respectively. At 77 K, the UTS is enhanced to 828 ± 99 MPa but the ductility is reduced by 10%. The combination of UTS and ductility at both tested temperatures is the best among the joints of CrMnFeCoNi and its derivatives. The reason for this unprecedented combination is explored by EBSD and atomistic simulation. Slip bands and low-density deformation twins are found in the deformed microstructure of the weld fractured at 300 K as evidenced from EBSD observation. High-density twins besides the slip bands are seen in the weld deformed at 77 K. Real-time atomistic deformation is revealed from MD simulation, including dislocation nucleation and its motion, the formation of twin boundaries, and the interaction between the dislocation and twin boundaries. The unprecedented combination of strength and ductility in laser welded NiCoCr joints provides significant promise of NiCoCr MEA for application in engineering structures, especially at cryogenic circumstances. • NiCoCr medium entropy alloy is successfully welded by laser welding for the first time. • Unprecedented combination of strength and ductility in laser welded NiCoCr joints is presented. • Deformation mechanisms in the weld at 300K include extensive slips and low-density deformation twins. • Extraordinary strength and ductility at 77K is attributed to deformation twins and the TB-dislocation interaction. • Real-time atomistic deformation mechanisms are prevailed from MD simulation. [ABSTRACT FROM AUTHOR]

Objective: The main objective of the study was to develop the Quantitative Structure- Activity Relationship (QSAR) and pharmacophore model by using data obtained from HT-29 cells to develop potent lead molecule for the scientific community., Materials and Methods: Common pharmacophore model, atom-based 3D-QSAR, and molecular dynamic (MD) simulation were carried out via computational techniques by using 4H-chromene derivatives., Results: The reliable common pharmacophoric hypothesis, DHH13 was generated and 3.95 survival value was also found. Furthermore, the statistically significant 3D-QSAR model was developed where r 2 =0.52 was found by using the Partial least squares (PLS) regression method. Phase predicted activity and Log GI 50 demonstrated an important atomic position in the structure of ligands to ascertain anti colon cancer activity. Also, MD simulation was carried out between top rank leads targeting IL-6 that provided better binding conformational and complex stability into the active pocket site of the target throughout the MD simulation., Conclusion: The outcome of this design shows that the pharmacophore model and 3D-QSAR might be helpful for researchers in the field of medicinal chemistry to design and develop potential anti colon cancer compounds., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Imidazole is one of the most explored and marketed azole utilized for the treatment of fungal infections. Lanosterol 14α-demethylase (Cytochrome P450DM) is the active target site for azole antifungals., Aim and Objective: This study emphasized on evaluation of a series of halogenated imidazole analogues using molecular docking studies for anti-Candidal activity. Furthermore, the model was refined by molecular dynamic simulation., Methods: Halogenated imidazole analogues (PS1-PS30) were obtained from literature for the study. The imidazole analogues were prepared using Chem sketch and molecular docking was performed using Molergo Virtual Docker program and ADMET study was carried out by using Accelry's Accord for Excel programme., Results: The docking study indicated that all the imidazole analogues (PS1-PS30) and standard drugs i.e., Ketoconazole, Miconazole and Clotrimazole possessed interaction with protein residue, heme cofactor and water molecule positioned above Heme cofactor of 14α-demethylase. Further, the ADMET study indicated that most of the halogenated imidazoles possessed good absorption, human intestinal absorption, aqueous solubility and blood brain penetration., Conclusion: Halogenated imidazole analogues may be used as potential lead molecules as 14α- demethylase inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)