Favorable Binding Free Energy Research Articles

Identification of Potential Inhibitors of Histone Deacetylase 6 Through Virtual Screening and Molecular Dynamics Simulation Approach: Implications in Neurodegenerative Diseases.

Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein-ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6-ligand complexes, confirming the stability of their interactions. The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

In silico studies on nicotinamide analogs as competitive inhibitors of nicotinamidase in methicillin-resistant Staphylococcus aureus.

Nicotinamidase/PncA is a member of the hydrolase enzyme family, catalyzing the de-amidation of nicotinamide (NM) to nicotinic acid (NA) via salvage pathway. Products are fed into Preiss-Handler pathway for NAD+ biosynthesis which is an important enzyme cofactor and crucial for redox balance in microorganisms. Pathogens like methicillin-resistant Staphylococcus aureus (MRSA) are NAD+ auxotroph and rely on their host environment for NAD+ precursors to synthesize NAD+. Mutations in nicotinamidase/PncA have been reported to be associated with resistance to pyrazinamide (PZA), a front-line anti-tubercular drug, underlying its importance as an important link in NAD+ biosynthesis network in pathogenic organisms such as MRSA. The conserved features of PncA and essentiality of salvage route in MRSA and the absence of this enzyme in humans and other eukaryotes are attractive options to explore therapeutics against this target. In this work, we have screened novel substrate analogs from the PubChem database using virtual screening approaches employing fingerprint tanimoto-based 2D similarity search against Staphylococcus aureus PncA (SaPncA). Identified compounds were further assessed using molecular dynamics simulations to investigate conformational stability and structural integrity. We propose two analogs, namely L28 and L33 with greater stability, favorable binding and strong binding free energies in MM-PBSA calculations. The strategy could provide an important clue in developing similar compound scaffolds as potent drug-like molecules against MRSA and other pathogenic species harboring this enzyme. Smaller scaffolds of these molecules could be attractive options for fragment-based derivatization for inhibitor discovery.

Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.

Virtual Screening and Molecular Dynamics Simulation to Identify Inhibitors of the m6A-RNA Reader Protein YTHDC1

YTHDC1 (YTH domain containing 1), a crucial reader protein of N6-methyladenosine (m6A) mRNA, plays a critical role in various cellular functions and is considered a promising target for therapeutic intervention in acute myeloid leukemia and other cancers. In this study, we identified orthosteric small-molecule ligands for YTHDC1. Using a molecular docking approach, we screened the eMolecules database and recognized 15 top-ranked ligands. Subsequently, molecular dynamics simulations and MM/PBSA analysis were used to assess the stability and binding free energy of these potential hit compounds in complex with YTHDC1. Notably, five compounds with IDs of ZINC82121447, ZINC02170552, ZINC65274016, ZINC10763862, and ZINC02412146 exhibited high binding affinities and favorable binding free energies. The results also showed that these compounds formed strong hydrogen bonds with residues SER378, ASN363, and ASN367 and interacted with the aromatic cage of the YTHDC1 reader protein through TRP377, TRP428, and hydrophobic residue LEU439. To assess their viability as lead compounds, we conducted absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies to reveal promising features for these identified small molecules, shedding light on their pharmacokinetic and safety profiles.

Asymmetric Carbene-Alkyne Metathesis-Mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker.

This study introduces a novel approach for synthesizing Benzoxazine-centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.

The Prediction of LptA and LptC Protein-Protein Interactions and Virtual Screening for Potential Inhibitors.

Antibiotic resistance in Gram-negative bacteria remains one of the most pressing challenges to global public health. Blocking the transportation of lipopolysaccharides (LPS), a crucial component of the outer membrane of Gram-negative bacteria, is considered a promising strategy for drug discovery. In the transportation process of LPS, two components of the LPS transport (Lpt) complex, LptA and LptC, are responsible for shuttling LPS across the periplasm to the outer membrane, highlighting their potential as targets for antibacterial drug development. In the current study, a protein-protein interaction (PPI) model of LptA and LptC was constructed, and a molecular screening strategy was employed to search a protein-protein interaction compound library. The screening results indicated that compound 18593 exhibits favorable binding free energy with LptA and LptC. In comparison with the molecular dynamics (MD) simulations on currently known inhibitors, compound 18593 shows more stable target binding ability at the same level. The current study suggests that compound 18593 may exhibit an inhibitory effect on the LPS transport process, making it a promising hit compound for further research.

Asymmetric Carbene‐Alkyne Metathesis‐Mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker

AbstractThis study introduces a novel approach for synthesizing Benzoxazine‐centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN.

Therapeutic potential of earthworm-derived proteins: Targeting NEDD4 for cardiovascular disease intervention

Targeting neuronal precursor cell-expressed developmentally down-regulated 4 (NEDD4) offers a promising strategy for cardiovascular therapies. NEDD4, a ubiquitin ligase enzyme, is crucial in protein degradation and cellular signaling. Earthworms (Lumbricus genus) are noteworthy for their rich biochemical composition and pharmacological properties. This study investigated the interactions between Lumbricus-derived proteins and NEDD4 to identify potential cardiovascular therapeutic candidates. Using advanced computational techniques, including 3D structure modeling, protein-protein docking simulations, 100 ns molecular dynamics (MD) simulations, and Molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, we assessed the binding affinities and functional impacts of these proteins on NEDD4 activity. The findings indicated that Lumbricus-derived proteins such as Lumbrokinase, heat shock protein, and elongation factor 1 (EF-1)-alpha showed activities similar to standard antagonists in modulating NEDD4. These results aligned with previous studies showing the inhibitory effects of heat shock protein and EF-1 on NEDD4 ubiquitination and ligase activity. Additionally, MM/PBSA calculations revealed favorable binding free energies for these compounds, underscoring their therapeutic potential in cardiovascular diseases. In conclusion, this study highlighted the potential of Lumbricus-derived compounds in cardiovascular disease therapy via the NEDD4 pathway, warranting further biochemical and preclinical validation and exploring broader therapeutic applications.

Conformational Properties of Aβ Peptide Oligomers in Aqueous Ionic Liquid Solution: Insights from Molecular Simulation Studies.

Alzheimer's disease is a progressive irreversible neurological disorder with abnormal extracellular deposition of amyloid β (Aβ) peptides in the brain. We have carried out atomistic molecular dynamics simulations to investigate the size-dependent conformational properties of aggregated Aβ oligomers of different orders, namely, pentamer [O(5)], decamer [O(10)], and hexadecamer [O(16)] in aqueous solutions containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). The calculations revealed reduced peptide conformational fluctuations in O(5) and O(10) in the presence of the IL. In contrast, the higher order oligomer [O(16)] has been found to exhibit greater structural distortion due to enhanced flexibilities of its peptide units in the presence of the IL. Based on the distributions of the solvent (water) and the cosolvent (IL) components, it is demonstrated that exchange of water by the IL ion pairs at the exterior surface of the oligomers primarily occurs beyond the first layer of surface-bound water molecules. Importantly, a reduced number of relatively weaker peptide salt bridges have been found in O(16) in binary water-IL solution as compared to the other two smaller-sized oligomers [O(5) and O(10)]. Such differential influence of the IL on peptide salt bridges results in less favorable binding free energies of peptide monomers to O(16), which leads to its greater structural distortion and reduced stability compared to those of O(5) and O(10).

Molecular Design of Novel Inhibitor by Targeting IL-6Rα using Combined Pharmacophore and Experimentally Verified Plant Products with Scaffold-Hopping Techniques: A Dual Therapeutic Strategy for COVID-19 and Cancer.

The IL-6/IL-6R/gp130 complex serves as a significant indicator of cytokine release syndrome in COVID-19 and chronic inflammation, increasing the risk of cancer. Therefore, we identified IL-6Rα as a potential target to block gp130 interaction. Notably, there has been no reception of approval for an orally available drug to serve this purpose, to date. In this study, we targeted IL-6Rα to inhibit IL-6Rα/gp130 interaction. The selection of the lead candidate L821 involved the amalgamation of three drug discovery approaches. This library was screened employing tertiary structure-based pharmacophore models followed by molecular docking models, scaffold-hopping, MM/PBSA as well as MM/GBSA analysis, and assessments of pKi and ADMET properties. After evaluating the binding interactions with key amino acids, 15 potential ligands were chosen, with the top ligand undergoing further investigation by means of molecular dynamics simulations. Considering the stability of the complexes, the strong interactions observed between ligand and residues of IL-6Rα/gp130, and the favorable binding free energy calculations, L821 emerged as the prime candidate for inhibiting IL-6Rα. Notably, L821 exhibited a docking-based binding affinity of -9.5 kcal/mol. Our study presents L821 as a promising inhibitor for future in vitro analysis, potentially combatting SARS-CoV-2-related cytokine storms and serving as an oncogenic drug therapy.

Derivates of 1,6-dihyadroazaazulenes as inhibitors of tyrosine kinases BCR-ABL1 wild type and mutant T315I: a molecular dynamics approach

The protein tyrosine kinase (PTK) produced by the BCR-ABL1 gene has generated significant interest in the development of inhibitors since the presence of punctual mutations causes resistance to currently approved drugs, mainly the T315I mutation has been the most difficult to address. In this work, derivatives of 1,6-dihydroazaazulenes are studied as possible inhibitors of this PTK in its wild form and the mutant T315I. The recognition of the ligands was explored through molecular docking, and the stability of the complexes and their evolution over time was studied using molecular dynamics (MD) simulations. Our results show that complexes are energetically stable and reside on the ATP binding site in all cases during the MD experiments. Interestingly, a few of our proposed ligands presented greater affinity for T315I, finding more favorable binding free energies (ΔG) than the reference drug axitinib. Furthermore, they may act as inhibitors for both isoforms. Our findings are promising because mutation of T315I does not prevent ligand recognition, as detailed in this work, which is very important to conduct further experimental research. Communicated by Ramaswamy H. Sarma

Repurposing of approved drugs for targeting CDK4/6 and aromatase protein using molecular docking and molecular dynamics studies.

Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast cancer, estrogen-receptor positive (ER+) is the most diagnosed. Estrogen upregulates cyclin D1, which in turn promotes the activity of CDK4/6 and facilitates cell cycle progression. To address this, the first-line treatment for ER+ breast cancer focuses on inhibiting estrogen production by targeting aromatase, the enzyme responsible for the rate-limiting step in estrogen synthesis. Thus, combining CDK4/6 inhibitors with aromatase inhibitors has emerged as a crucial treatment strategy for this type of breast cancer. This approach effectively suppresses estrogen biosynthesis and controls uncontrolled cell proliferation, significantly improving overall survival rates and delayed disease progression. This study aimed to identify compounds that are likely to inhibit CDK4/6 and aromatase simultaneously by using a structure-based drug design strategy. 12,432 approved and investigational drugs were prepared and docked into the active site of CDK6 using HTVS and XP docking modes of Glide resulting in 277 compounds with docking scores ≤ -7 kcal/mol. These compounds were docked into aromatase enzyme using XP mode to give seven drugs with docking scores≤ -6.001 kcal/mol. Furthermore, the shortlisted drugs were docked against CDK4 showing docking scores ranging from -3.254 to -8.254 kcal/mol. Moreover, MM-GBSA for the top seven drugs was calculated. Four drugs, namely ellagic acid, carazolol, dantron, and apomorphine, demonstrated good binding affinity to all three protein targets CDK4/6 and aromatase. Specifically, they exhibited favourable binding free energy with CDK6, with values of -51.92, -53.90, -50.22, and -60.97 kcal/mol, respectively. Among these drugs, apomorphine displayed the most favourable binding free energy with all three protein targets. To further evaluate the stability of the interaction, apomorphine was subjected to a 100 ns molecular dynamics simulation with CDK6. The results indicated the formation of a stable ligand-protein complex. While the results obtained from the MM-GBSA calculation of the binding free energies of the MD conformations of apomorphine showed less favourable binding free energy compared to that obtained post-docking. All these computational findings will provide better structural insight for the development of CDK4/6 and aromatase multi-target inhibitors.

SBS 3.1, a novel natural product small molecule regulates TNF-α-induced NF-κB activation and key signals of inflammation to promote apoptosis in lung cancer tumour microenvironment

Chronic inflammation leads to many maladies in lung cancer. Tumor necrosis factor-alpha (T NF- α), a pleiotropic proinflammatory cytokine regulates the activation of the nuclear factor-κB (NF-κB) to drive many physiological and pathological signaling pathways in inflammation and cancer apoptosis. This study identified a novel natural product to inhibit T NF-α induced NF-κB activation. Virtual docking of ZINC natural product library and computational modeling analysis showed compounds that target crucial amino acid residues on p50 protein involved in DNA binding. Molecular dynamic simulation showed, compound SBS-3.1, as the best lead compound that binds efficiently and stably with p50 protein. MMP BSA analysis of the lead compound predicted a favorable binding free energy. The compound inhibited the proliferations of T NF-α induced A-549 with a GI50 value of 30.53 μM. SBS-3.1 decreased the percentage of T NF-α induced NF-κB-65, p38 and ERK1/2 positive lung cancer cells, while the apoptosis in these cells were elevated. In summary, SBS-3.1, a natural product, was identified as the lead compound targeting Rel-homology region of p50. Inhibition of NF-κB and inflammatory signals by SBS 3.1 promoted apoptosis in lung cancer. Further research can bring new therapeutic strategies for treating inflammation associated T ME of lung cancer cells. Communicated by Ramaswamy H. Sarma

Cheminformatics Strategies Unlock Marburg Virus VP35 Inhibitors from Natural Compound Library.

The Ebola virus and its close relative, the Marburg virus, both belong to the family Filoviridae and are highly hazardous and contagious viruses. With a mortality rate ranging from 23% to 90%, depending on the specific outbreak, the development of effective antiviral interventions is crucial for reducing fatalities and mitigating the impact of Marburg virus outbreaks. In this investigation, a virtual screening approach was employed to evaluate 2042 natural compounds for their potential interactions with the VP35 protein of the Marburg virus. Average and worst binding energies were calculated for all 20 poses, and compounds that exhibited binding energies <-6 kcal/mol in both criteria were selected for further analysis. Based on binding energies, only six compounds (Estradiol benzoate, INVEGA (paliperidone), Isosilybin, Protopanaxadiol, Permethrin, and Bufalin) were selected for subsequent investigations, focusing on interaction analysis. Among these selected compounds, Estradiol benzoate, INVEGA (paliperidone), and Isosilybin showed strong hydrogen bonds, while the others did not. In this study, the compounds Myricetin, Isosilybin, and Estradiol benzoate were subjected to a molecular dynamics (MD) simulation and free binding energy calculation using MM/GBSA analysis. The reference component Myricetin served as a control. Estradiol benzoate exhibited the most stable and consistent root-mean-square deviation (RMSD) values, whereas Isosilybin showed significant fluctuations in RMSD. The compound Estradiol benzoate exhibited the lowest ΔG binding free energy (-22.89 kcal/mol), surpassing the control compound's binding energy (-9.29 kcal/mol). Overall, this investigation suggested that Estradiol benzoate possesses favorable binding free energies, indicating a potential inhibitory mechanism against the VP35 protein of the Marburg virus. The study proposes that these natural compounds could serve as a therapeutic option for preventing Marburg virus infection. However, experimental validation is required to further corroborate these findings.

In Silico Discovery of Potential Inhibitors Targeting the RNA Binding Loop of ADAR2 and 5-HT2CR from Traditional Chinese Natural Compounds.

Adenosine deaminase acting on RNA 2 (ADAR2) is an important enzyme involved in RNA editing processes, particularly in the conversion of adenosine to inosine in RNA molecules. Dysregulation of ADAR2 activity has been implicated in various diseases, including neurological disorders (including schizophrenia), inflammatory disorders, viral infections, and cancers. Therefore, targeting ADAR2 with small molecules presents a promising therapeutic strategy for modulating RNA editing and potentially treating associated pathologies. However, there are limited compounds that effectively inhibit ADAR2 reactions. This study therefore employed computational approaches to virtually screen natural compounds from the traditional Chinese medicine (TCM) library. The shortlisted compounds demonstrated a stronger binding affinity to the ADAR2 (<-9.5 kcal/mol) than the known inhibitor, 8-azanebularine (-6.8 kcal/mol). The topmost compounds were also observed to possess high binding affinity towards 5-HT2CR with binding energies ranging from -7.8 to -12.9 kcal/mol. Further subjecting the top ADAR2-ligand complexes to molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed that five potential hit compounds comprising ZINC000014637370, ZINC000085593577, ZINC000042890265, ZINC000039183320, and ZINC000101100339 had favorable binding free energies of -174.911, -137.369, -117.236, -67.023, and -64.913 kJ/mol, respectively, with the human ADAR2 protein. Residues Lys350, Cys377, Glu396, Cys451, Arg455, Ser486, Gln488, and Arg510 were also predicted to be crucial in ligand recognition and binding. This finding will provide valuable insights into the molecular interactions between ADAR2 and small molecules, aiding in the design of future ADAR2 inhibitors with potential therapeutic applications. The potential lead compounds were also profiled to have insignificant toxicities. A structural similarity search via DrugBank revealed that ZINC000039183320 and ZINC000014637370 were similar to naringin and naringenin, which are known adenosine deaminase (ADA) inhibitors. These potential novel ADAR2 inhibitors identified herein may be beneficial in treating several neurological disorders, cancers, viral infections, and inflammatory disorders caused by ADAR2 after experimental validation.

Synthesis and docking studies of new 5-bromoindole-2-carboxylic acid oxadiazole derivatives as EGFR inhibitors

The current study reports the design and synthesis of novel oxadiazole derivatives of 5-bromoindole-2-carboxylic acid and their molecular docking properties. In order to determine the structure of the new oxadiazole derivatives (3, 4a, 4b), a number of spectroscopic techniques (IR and 1HNMR) were employed. Molecular docking analysis indicated that compounds 3, 4a, 4b showed favorable binding free energy against the EGFR tyrosine kinase domain. None of these compounds appeared to suppress cytochrome P450, and all of them showed appropriate absorption levels. Moreover, they did not exhibit any hepatotoxicity when tested in vitro. Compound 4a Reported to have the highest stability, with a good net binding energy, and an excellent binding energy with hot amino acids. Dipole moment is also rather high. This result is an indication of compound 4a is with superior capacity to create hydrogen bonds over erlotinib. Likewise, compound 4a was found to be the most stable in its interaction with EGFR tyrosine kinase. Finally, molecular dynamic simulation revealed excellent outcomes for compound 4a.

In silico screening of a series of 1,6-disubstituted 1H-pyrazolo[3,4-d]pyrimidines as potential selective inhibitors of the Janus kinase 3

Rheumatoid arthritis is a common chronic disabling inflammatory disease that is characterized by inflammation of the synovial membrane and leads to discomfort. In the current study, twenty-seven 1,6-disubstituted 1H-pyrazolo[3,4-d]pyrimidines were tested as potential selective inhibitors of the tyrosine-protein kinase JAK3 using a number of molecular modeling methods. The activity of the screened derivatives was statistically quantified using multiple linear regression and artificial neural networks. To assess the quality, robustness, and predictability of the generated models, the leave-one-out cross-validation method was applied with favorable results (Q2 = 0.75) and Y-randomization. In addition, the evaluation of the predictive ability of the established model was confirmed by means of an external validation using a composite test set and an applicability domain approach. The covalent docking indicated that the tested 1H-pyrazolo[3,4-d]pyrimidines containing the acrylic aldehyde moiety had irreversible interaction with the residue Cys909 in the active sites of the tyrosine-protein kinase JAK3 by Michael addition. The molecular dynamics for three selected derivatives (compounds 9, 12, and 18) were used to verify the covalent docking by determining the stability of hydrogen bonding interactions with active sites, which are needed to stop tyrosine-protein kinase JAK3. The results obtained showed that the tested compounds containing acrylic aldehyde moiety had favorable binding free energies, indicating a strong affinity for the JAK3 enzyme. Overall, this current study suggests that the tested compounds containing the acrylic aldehyde moiety have the potential to act as anti-JAK3 inhibitors. They could be explored further to be used as treatment options for rheumatoid arthritis. Communicated by Ramaswamy H. Sarma.

In Silico Analysis of a GH3 β-Glucosidase from Microcystis aeruginosa CACIAM 03.

Cyanobacteria are rich sources of secondary metabolites and have the potential to be excellent industrial enzyme producers. β-glucosidases are extensively employed in processing biomass degradation as they mediate the most crucial step of bioconversion of cellobiose (CBI), hence controlling the efficiency and global rate of biomass hydrolysis. However, the production and availability of these enzymes derived from cyanobacteria remains limited. In this study, we evaluated the β-glucosidase from Microcystis aeruginosa CACIAM 03 (MaBgl3) and its potential for bioconversion of cellulosic biomass by analyzing primary/secondary structures, predicting physicochemical properties, homology modeling, molecular docking, and simulations of molecular dynamics (MD). The results showed that MaBgl3 derives from an N-terminal domain folded as a distorted β-barrel, which contains the conserved His-Asp catalytic dyad often found in glycosylases of the GH3 family. The molecular docking results showed relevant interactions with Asp81, Ala271 and Arg444 residues that contribute to the binding process during MD simulation. Moreover, the MD simulation of the MaBgl3 was stable, shown by analyzing the root mean square deviation (RMSD) values and observing favorable binding free energy in both complexes. In addition, experimental data suggest that MaBgl3 could be a potential enzyme for cellobiose-hydrolyzing degradation.

Structural and molecular insights into tacrine-benzofuran hybrid induced inhibition of amyloid-β peptide aggregation and BACE1 activity

Amyloid-β (Aβ) aggregation and β-amyloid precursor protein cleaving enzyme 1 (BACE1) are the potential therapeutic drug targets for Alzheimer’s disease (AD). A recent study highlighted that tacrine-benzofuran hybrid C1 displayed anti-aggregation activity against Aβ42 peptide and inhibit BACE1 activity. However, the inhibition mechanism of C1 against Aβ42 aggregation and BACE1 activity remains unclear. Thus, molecular dynamics (MD) simulations of Aβ42 monomer and BACE1 with and without C1 were performed to inspect the inhibitory mechanism of C1 against Aβ42 aggregation and BACE1 activity. In addition, a ligand-based virtual screening followed by MD simulations was employed to explore potent new small-molecule dual inhibitors of Aβ42 aggregation and BACE1 activity. MD simulations highlighted that C1 promotes the non aggregating helical conformation in Aβ42 and destabilizes D23–K28 salt bridge that plays a vital role in the self-aggregation of Aβ42. C1 displays a favourable binding free energy (–50.7 ± 7.3 kcal/mol) with Aβ42 monomer and preferentially binds to the central hydrophobic core (CHC) residues. MD simulations highlighted that C1 strongly interacted with the BACE1 active site (Asp32 and Asp228) and active pockets. The scrutiny of interatomic distances among key residues of BACE1 highlighted the close flap (non-active) position in BACE1 on the incorporation of C1. The MD simulations explain the observed high inhibitory activity of C1 against Aβ aggregation and BACE1 in the in vitro studies. The ligand-based virtual screening followed by MD simulations identified CHEMBL2019027 (C2) as a promising dual inhibitor of Aβ42 aggregation and BACE1 activity. Communicated by Ramaswamy H. Sarma

Microscopic Understanding of the Conformational Stability of the Aggregated Nonamyloid β Components of α-Synuclein.

Self-association of α-synuclein peptides into oligomeric species and ordered amyloid fibrils is associated with Parkinson's disease, a progressive neurodegenerative disorder. In particular, the peptide domain formed between the residues Glu-61 (or E61) and Val-95 (or V95) of α-synuclein, typically termed the "nonamyloid β component" (NAC), is known to play critical roles in forming aggregated structures. In this work, we have employed molecular dynamics simulations to explore the conformational properties and relative stabilities of aggregated protofilaments of different orders, namely, tetramer (P(4)), hexamer (P(6)), octamer (P(8)), decamer (P(10)), dodecamer (P(12)), and tetradecamer (P(14)), formed by the NAC domains of α-synuclein. Besides, center-of-mass pulling and umbrella sampling simulation methods have also been employed to characterize the mechanistic pathway of peptide association/dissociation and the corresponding free energy profiles. Structural analysis showed that the disordered C-terminal loop and the central core regions of the peptide units lead to more flexible and distorted structures of the lower order protofilaments (P(4) and P(6)) as compared to the higher order ones. Interestingly, our calculation shows the presence of multiple distinctly populated conformational states for the lower order protofilament P(4), which may drive the oligomerization process along multiple pathways to form different polymorphic α-synuclein fibrillar structures. It is further observed that the nonpolar interaction between the peptides and the corresponding nonpolar solvation free energy play a dominant role in stabilizing the aggregated protofilaments. Importantly, our result showed that reduced cooperativity during the binding of a peptide unit beyond a critical size of the protofilament (P(12)) leads to less favorable binding free energy of a peptide.