Molecular Mechanics Poisson-Boltzmann Surface Area Research Articles

Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics simulations

ABSTRACT The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells’ signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes. We considered R406, the active component of fostamatinib, as a control. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations demonstrated the lead1 ( = -30.35 kcal/mol) exhibited a similar binding free energy as the control (= −29.82 kcal/mol). The Syk stabilizing effect of lead1 was also indicated in its network features, sampling space, and residual correlation motion analysis. We further generated 100 structural analogues of lead1 using deep learning, and one of the analogues displayed a better binding free energy (= −47.58 kcal/mol) compared to the control or lead1, facilitated by more favourable van der Waals interactions and lesser binding-opposing net polar forces. This analogue may be further exploited to develop effective therapeutics against Syk-associated diseases after validation in vitro and in vivo.

Inhibitor screening for volume-sensitive LRRC8A chloride channel

Leucine-rich repeat-containing protein 8 A (LRRC8A) protein is a critical member of volume-regulated anion channels. It plays a critical roles in the regulation of cellular volume and involves in the development of diseases like osteoarthritis. Screening of lead compounds to modulate its function may provide potential therapeutics of related diseases. Here, we employ virtual screening techniques and molecular dynamics (MD) simulation to screen potential inhibitors against LRRC8A. LRRC8A was regarded as the drug target to investigate potential compounds from the ZINC15 database via molecular docking. The final compound was selected among the top 10 Autodock Vina score (–8.8 Kcal/mol) with the ZINC ID ZINC000018195627 after druggability prediction. The docked complex from the virtual screening was subjected to MD simulation to analyze the stability of the LRRC8A protein–ligand complex, with parameters including root mean square deviation, root mean square fluctuation and radius of gyration. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method was further employed to predict the binding free energies from MD simulation trajectory. Our study provides insightful analysis for the potential compound to modulate LRRC8A and lay the foundation of therapeutics development against osteoarthritis. Communicated by Ramaswamy H. Sarma

Exploring the Novel Anticonvulsant Phytochemicals from Glycyrrhiza glabra: An In Silico Approach

AbstractComputational methods like molecular docking, pharmacokinetic study, molecular dynamic (MD) simulation and Molecular Mechanics‐Poisson‐Boltzmann Surface Area (MM‐PBSA) were used to investigate the ability of Glycyrrhiza glabra phytoconstituents to modulate the activity of GABA‐A receptor. The docking studies suggested that both Kanzonol U and Glabrol, have shown superior binding abilities, as evident by their binding energies of −11.8 and −11.4 kcal/mol, respectively, as compared to diazepam (−10.0 kcal/mol), which is an allosteric modulator of GABA‐A. Only nine constituents were identified as the blood‐brain barrier permeants in the SwissADME investigation, with binding energy≤−10.0 kcal/mol. The docking results were further strengthened by MD simulation which showed that the Kanzonol U and Glabrol complex displayed good conformational stability with an average RMSD of 0.20 nm. Additionally, MM‐PBSA outcomes revealed that these phytochemicals as the most potent GABA‐A modulators. All these investigations suggest that the phytochemicals Kanzonol U and Glabrol may produce a promising antiepileptic effect.

Screening of potent inhibitor from Aquilaria malaccensis Lam. against arachidonic inflammatory enzymes: an insight from molecular docking, ADMET, molecular dynamics simulation and MM-PBSA approaches

The three primary enzymes COX (cyclooxygenase), LOX (lipoxygenase) and CYT-P450 (cytochrome P450), which are part of the arachidonic inflammatory pathway, play crucial role in the development of asthma, rheumatoid arthritis and cardiovascular diseases. Ethnomedicinally, plant-derived chemicals have a major role in the treatment of fatal illnesses. Aquilaria malaccensis Lam. widely known as agarwood is prized for its fragrance and therapeutic properties. The phytochemicals and extracts of this plant have significant healing properties in the treatment of serious illnesses. In the current work, an in-silico approach including molecular docking, ADMET (absorption, distribution, metabolism, excretion and toxicity), molecular dynamics (MD) simulation and molecular mechanics/Poisson–Boltzmann surface area (MM-PBSA) was performed to screen 33 bioactive compounds from this plant against COX-2 and 5-LOX in order to find the most effective inhibitor. 2-(2-Phenylethyl)chromone was found to inhibit both 5-LOX and COX-2, showing the highest binding affinities (−9.1 kcal/mol and −9.0 kcal/mol, respectively) than standard Ibuprofen and nordihydroguaiaretic acid (NDGA). 2-(2-Phenylethyl)chromone showed the highest drug-likeness score and low risk of toxicity compared to other phytochemicals. MD modeling and MM-PBSA calculations showed that 2-(2-Phenylethyl)chromone had a strong persistent binding interaction with 5-LOX than COX-2, and this interaction is comparable to the bounded standards Ibuprofen and NDGA. From this study, we may infer that the 2-(2-Phenylethyl)chromone can serve as a potent inhibitor and has scope to be employed in the treatment of inflammatory ailments. Communicated by Ramaswamy H. Sarma

Unlocking potential inhibitors for Bruton's tyrosine kinase through in-silico drug repurposing strategies

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery.

Exploring sterol transportation behavior of the Niemann-Pick C1-like 1 protein with V55L mutation: Sterol-NPC1L1 N-terminal binding energy estimation via molecular dynamics simulations

ABSTRACT The Niemann-Pick C1-like 1 (NPC1L1) protein facilitates cholesterol absorption in the small intestine and mediates the absorption of other sterols, including vitamins E, vitamin K1, and coenzyme Q10 (CoQ10). Ezetimibe is a drug used to treat high blood cholesterol and lipid abnormalities. However, V55L/I1223N and non-conserved V55 mutations in humans and rats, respectively, have been linked to ezetimibe insensitivity. In this study, molecular modeling, which combines the molecular dynamics simulations with the molecular mechanics Poisson-Boltzmann surface area approach, was used to estimate the change in the binding free energy of the NPC1L1 N-terminal domain (NTD) owing to the V55L mutation, Further, free energy changes for the three sterols namely, vitamin E, vitamin K1, and CoQ10 were estimated. The current study found that the V55L mutation reduced the cholesterol to NPC1L1-NTD binding free energy, which compensates for the decreased cholesterol passage through the putative tunnel induced by the ezetimibe. Therefore, molecular modeling of the free energy changes owing to mutations can successfully provide insights into the intricate details of drug inhibitors.

Finding small molecular compounds to decrease trimethylamine oxide levels in atherosclerosis by virtual screening

Abstract The intestinal microbial metabolite trimethylamine oxide (TMAO) affects the formation and development of atherosclerosis (AS). The design and development of an effective targeted drug to reduce serum TMAO levels may provide new avenues for inhibiting AS morbidity. Target genes that may elevate TMAO levels in patients with AS were explored using bioinformatics, virtual screening, and molecular dynamics (MD). We expected these genes to indicate potential TMAO inhibitors. Of these genes, hFMO3 was responsible for increasing TMAO levels. Four small-molecule compounds (SMC-1, SMC-2, SMC-3, and SMC-4) with the lowest binding energy and CGenFF penalty < 10 were connected to the main binding pocket of hFMO3 by hydrogen and/or cation–pi interactions. A 100 ns MD simulation showed that the four systems quickly reached equilibrium. The root mean square deviation of all four small-molecule compounds was less than 0.35 nm, that of the four ligand complexes was less than 0.40 nm, and the average deviations of each amino acid residue from the reference position over time did not differ. Molecular mechanics Poisson–Boltzmann surface area analyses showed that SMC-2, SMC-3, and SMC-4 bound very well to hFMO3, and the energy contribution of the key residues LEU40 and GLU32 was more remarkable in SMC-2, SMC-3, and SMC-4. These four small-molecule compounds may be useful as targeted drugs to reduce serum TMAO levels, inhibiting atherosclerosis formation.

Design, Synthesis, Pharmacological Activities, Structure-Activity Relationship, and In Silico Studies of Novel 5-Substituted-2-(morpholinoimino)-thiazolidin-4-ones.

This study is aimed to synthesize morpholine- and thiazolidine-based novel 5-(substituted)benzylidene)-2-(morpholinoimino)-3-phenylthiazolidin-4-ones (3-26) and characterized by molecular spectroscopy. The synthesized compounds were subjected to antioxidant activity with anticholinesterase, tyrosinase, and urease inhibition activities and evaluated the structure-activity relationship (SAR) of enzyme inhibition activities. Compound 11 was found to be the most active antioxidant. In anticholinesterase inhibition, compound 12 (IC50: 17.41 ± 0.22 μM) was the most active against AChE, while compounds 3-26 ( except 3, 8, and 17) showed notable activity against BChE. Compounds 17 (IC50: 3.22 ± 0.70 mM), 15 (IC50: 5.19 ± 0.03 mM), 24 (IC50: 7.21 ± 0.27 mM), 23 (IC50: 8.05 ± 0.11 mM), 14 (IC50: 8.10 ± 0.22 mM), 25 (IC50: 8.40 ± 0.64 mM), 26 (IC50: 8.76 ± 0.90 mM), and 22 (IC50: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds 20 (IC50: 16.79 ± 0.19 μM), 19 (IC50: 18.25 ± 0.50 μM), 18 (IC50: 20.24 ± 0.77 μM), 26 (IC50: 21.51 ± 0.44 μM), 25 (IC50: 21.70 ± 0.06 μM), and 24 (IC50: 22.49 ± 0.11 μM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between (1-26) compounds and enzymes at the molecular level. According to the results of this study, the synthesized compounds exhibited a better binding affinity toward these enzymes compared to the positive control. Further, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy and molecular dynamics (MD) simulation analyses were performed for AChE with compound 26, which showed high inhibitory activity in silico and in vitro studies. In conclusion, novel morpholine and thiazolidine-based derivative compounds may be pharmacologically effective agents for AChE, BChE, tyrosinase, and urease enzymes.

Microsecond dynamics of H10N7 influenza neuraminidase reveals the plasticity of loop regions and drug resistance due to the R292K mutation.

At the beginning of the last century, multiple pandemics caused by influenza (flu) viruses severely impacted public health. Despite the development of vaccinations and antiviral medications to prevent and control impending flu outbreaks, unforeseen novel strains and continuously evolving old strains continue to represent a serious threat to human life. Therefore, the recently identified H10N7, for which not much data is available for rational structure-based drug design, needs to be further explored. Here, we investigated the structural dynamics of neuraminidase N7 upon binding of inhibitors, and the drug resistance mechanisms against the oseltamivir (OTV) and laninamivir (LNV) antivirals due to the crucial R292K mutation on the N7 using the computational microscope, molecular dynamics (MD) simulations. In this study, each system underwent long 2 × 1 μs MD simulations to answer the conformational changes and drug resistance mechanisms. These long time-scale dynamics simulations and free energy landscapes demonstrated that the mutant systems showed a high degree of conformational variation compared to their wildtype (WT) counterparts, and the LNV-bound mutant exhibited an extended 150-loop conformation. Further, the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculation and MM/GBSA free energy decomposition were used to characterize the binding of OTV and LNV with WT, and R292K mutated N7, revealing the R292K mutation as drug-resistant, facilitated by a decline in binding interaction and a reduction in the dehydration penalty. Due to the broader binding pocket cavity of the smaller K292 mutant residue relative to the wildtype, the drug carboxylate to K292 hydrogen bonding was lost, and the area surrounding the K292 residue was more accessible to water molecules. This implies that drug resistance could be reduced by strengthening the hydrogen bond contacts between N7 inhibitors and altered N7, creating inhibitors that can form a hydrogen bond to the mutant K292, or preserving the closed cavity conformations.

Highly robust quantum mechanics and umbrella sampling studies on inclusion complexes of curcumin and β-cyclodextrin

The poor aqueous solubility of curcumin (CUR) obstructs its wide utilization in nutraceuticals, cosmetics, and pharmaceutical companies. This study is dedicated to investigate the stability of CUR inside the hydrophobic pocket of β-cyclodextrin (β-CD), hydroxypropyl-β-CD (HP-β-CD), and 2,6-Di-O-methyl-β-CD (DM-β-CD). Initially, molecular mechanics (MM) calculations and subsequently quantum mechanical (QM) calculations were performed on inclusion complexes to strengthen the MM results. We performed microsecond timescale MD simulations to observe the structural dynamics of CUR inside the cavity of CDs. We elucidated the most stable binding orientations of CUR inside the cavity of CDs based on binding free energy obtained from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and umbrella sampling simulations. Furthermore, the two-layered ONIOM (B3LYP/6-311+G(2d,p):PM7) method with CPCM implicit water model was used to derive the complete energetics and thermodynamics of inclusion complexes at 1:1 stoichiometry. Each inclusion reaction was exothermic and spontaneous. The chemical reactivity and kinetic stability of inclusion complexes were described by HOMO-LUMO molecular orbital energies. In conclusion, our studies revealed that HP-β-CD had the highest binding affinity for CUR with the most negative complexation energy (−6520.69 kJ/mol) and Gibb's free energy change (−6448.20 kJ/mol). The atomic-level investigation of noncovalent interactions between CUR and the hydroxypropyl groups in HP-β-CD/CUR complex may be helpful to drive new derivatives of HP-β-CD with better host capacity. The computational strategy adopted here might serve as a benchmark for increasing the solubility of numerous clinically significant molecules.

Impact of GSK199 and GSK106 binding on protein arginine deiminase IV stability and flexibility: A computational approach

Protein arginine deiminase IV (PAD4) is a potential target for diseases including rheumatoid arthritis and cancers. Currently, GSK199 is a potent, selective yet reversible PAD4 inhibitor. Its derivative, GSK106, on the other hand, was reported as an inactive compound when tested against PAD4 assay. Although they had similar skeleton, their impact towards PAD4 structural and flexibility is unknown. In order to fill the research gap, the impact of GSK199 and GSK106 binding towards PAD4 stability and flexibility is investigated via a combination of computational methods. Molecular docking indicates that GSK199 and GSK106 are capable to bind at PAD4 pocket by using its back door with −10.6 kcal/mol and −9.6 kcal/mol, respectively. The simulations of both complexes were stable throughout 100 ns. The structure of PAD4 exhibited a tighter packing in the presence of GSK106 compared to GSK199. The RMSF analysis demonstrates significant changes between the PAD4-GSK199 and PAD4-GSK106 simulations in the regions containing residues 136, 160, 220, 438, and 606. The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis shows a marked difference in binding free energies, with −11.339 kcal/mol for the PAD4-GSK199 complex and 1.063 kcal/mol for the PAD4-GSK106 complex. The hydrogen bond analysis revealed that the GSK199 and GSK106 binding to PAD4 are assisted by six hydrogen bonds and three hydrogen bonds, respectively. The visualisation of the MD simulations revealed that GSK199 remained in the PAD4 pocket, whereas GSK106 shifted away from the catalytic site. Meanwhile, molecular dockings of benzoyl arginine amide (BAEE) substrate have shown that BAEE is able to bind to PAD4 catalytic site when GSK106 was present but not when GSK199 occupied the site. Overall, combination of computational approaches successfully described the behaviour of binding pocket of PAD4 structure in the presence of the active and inactive compounds.

Identification of PPA1 inhibitor candidates for potential repurposing in cancer medicine.

Inorganic pyrophosphatase 1 (PPA1) is pivotal to cellular metabolism as it facilitates the hydrolysis of PPi-a by-product of various metabolic processes that influence cell growth and differentiation. Overexpression of PPA1 enzyme has been linked to diminished patient survival and was shown to influence tumor cell dynamics, thereby positioning it as a potential therapy target for a variety of cancers including colorectal cancer, diffuse large B-cell lymphoma, and lung adenocarcinoma. Despite this therapeutic promise, there are no known inhibitors of PPA1 as of today. In this study, we searched for potential PPA1 inhibitors using a molecular docking screen of 30 470 compounds with a history of clinical trials and/or US Food and Drug Administration approval. We specifically targeted the active pocket that coincides with the established catalytic domain. Our screen identified promising hits, which we further subjected to ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering. Subsequent molecular dynamics (MD) analyses were conducted on devazepide, quinotolast, and tarazepide-the three substances that successfully navigated all filters. MD analyses reinforced the stability of the protein-ligand complexes and confirmed ligand binding, as substantiated by our root mean square deviation, radius of gyration and secondary structures of proteins analyses. Furthermore, Molecular Mechanics Poisson-Boltzmann Surface Area calculations post-MD identified devazepide and quinotolast as showing higher binding affinities; being supported by principal component analysis, free energy landscape, and dynamic cross-correlation matrix results. Overall, our study reveals devazepide and quinotolast as potential candidates for PPA1 inhibition which could be considered for repurposing studies that need further experimental validation. These results not only reveal a potential for clinical repurposing for PPA1 inhibition but they also offer valuable insights into the development of future compounds for targeting the crucial PPA1 enzyme.

Plant derived active compounds of ayurvedic neurological formulation, Saraswatharishta as a potential dual leucine zipper kinase inhibitor: an in-silico study

Recent findings have highlighted the essential role of dual leucine zipper kinase (DLK) in neuronal degeneration. Saraswatharishta (SWRT), an ayurvedic formulation utilized in traditional Indian medicine, has demonstrated effectiveness in addressing neurodegenerative diseases. Herein, we aim to delve into the atomistic details of the mode of action of phytochemicals present in SWRT against DLK. Our screening process encompassed over 500 distinct phytochemicals derived from the main ingredients of the SWRT formulation. Through a comparative analysis of docking scores and relative poses, we successfully identified four novel compounds, which underwent further investigation via 2 × 500 ns long molecular dynamics (MD) simulations. Among the top four compounds, CID16066851 sourced from the Acorus calamus displayed the most stable complex with DLK. The molecular mechanics Poisson − Boltzmann surface area (MM-PBSA) calculations highlighted the significance of electrostatic and van der Waals interactions in the binding recognition process. Additionally, we identified key residues, namely Phe192, Leu243, Val139, and Leu141, as hotspots that predominantly govern the DLK-inhibitor interaction. Notably, the leading compounds are sourced from the Acorus calamus, Syzygium aromaticum, Zingiber officinale, and Anethum sowa plants present in the SWRT formulation. Overall, the findings of our study hold promise for future drug development endeavors combating neurodegenerative conditions. Communicated by Ramaswamy H. Sarma

Unveiling Neuroprotective Potential of Spice Plant-Derived Compounds against Alzheimer's Disease: Insights from Computational Studies.

Alzheimer's disease (AD) is a serious threat to the global health care system and is brought on by a series of factors that cause neuronal dysfunction and impairment in memory and cognitive decline. This study investigated the therapeutic potential of phytochemicals that belong to the ten regularly used spice plants, based on their binding affinity with AD-associated proteins. Comprehensive docking studies were performed using AutoDock Vina in PyRx followed by molecular dynamic (MD) simulations using AMBER 14. The docking study of the chosen molecules revealed the binding energies of their interactions with the target proteins, while MD simulations were carried out to verify the steadiness of bound complexes. Through the Lipinski filter and admetSAR analysis, the chosen compounds' pharmacokinetic characteristics and drug likeness were also examined. The pharmacophore mapping study was also done and analyzed for best selected molecules. Additionally, principal component analysis (PCA) was used to examine how the general motion of the protein changed. The results showed quercetin and myricetin to be potential inhibitors of AChE and alpha-amyrin and beta-chlorogenin to be potential inhibitors of BuChE, exhibiting best binding energies comparable to those of donepezil, used as a positive control. The multiple descriptors from the simulation study, root mean square deviation (RMSD), root mean square fluctuation (RMSF), hydrogen bond, radius of gyration (Rg), and solvent-accessible surface areas (SASA), confirm the stable nature of the protein-ligand complexes. Molecular mechanic Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations indicated the energetically favorable binding of the ligands to the protein. Finally, according to pharmacokinetic properties and drug likeness, characteristics showed that quercetin and myricetin for AChE and alpha-amyrin and beta-chlorogenin for BuChE were found to be the most effective agents for treating the AD.

Identification of novel metallo-β-lactamases inhibitors using ligand-based pharmacophore modelling and structure-based virtual screening

Metallo-β-lactamases (MBLs) are a group of enzymes that hydrolyze the most commonly used β-lactam-based antibiotics, leading to the development of multi-drug resistance. The three main clinically relevant groups of these enzymes are IMP, VIM, and NDM. This study aims to introduce potent novel overlapped candidates from a ZINC database retrieved from the 200,583-member natural library against the active sites of IMP-1, VIM-2, and NDM-1 through a straightforward computational workflow using virtual screening approaches. The screening pipeline started by assessing Lipinski’s rule of five (RO5), drug-likeness, and pan-assay interference compounds (PAINS) which were used to generate a pharmacophore model using D-captopril as a standard inhibitor. The process was followed by the consensus docking protocol and molecular dynamic (MD) simulation combined with the molecular mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method to compute the total binding free energy and evaluate the binding characteristics. The absorption, distribution, metabolism, elimination, and toxicity (ADMET) profiles of the compounds were also analyzed, and the search space decreased to the final two inhibitory candidates for B1 subclass MBLs, which fulfilled all criteria for further experimental evaluation. Communicated by Ramaswamy H. Sarma

Potent multi-target natural inhibitors against SARS-CoV-2 from medicinal plants of the Himalaya: a discovery from hybrid machine learning, chemoinformatics, and simulation assisted screening

The emergence and immune evasion ability of SARS-CoV-2 Omicron strains, mainly BA.5.2 and BF.7 and other variants of concern have raised global apprehensions. With this context, the discovery of multitarget inhibitors may be proven more comprehensive paradigm than its one-drug-to-one target counterpart. In the current study, a library of 271 phytochemicals from 25 medicinal plants from the Indian Himalayan Region has been virtually screened against SARS-CoV-2 by targeting nine virus proteins, viz., papain-like protease, main protease, nsp12, helicase, nsp14, nsp15, nsp16, envelope, and nucleocapsid for screening of a multi-target inhibitor against the viral replication. Initially, 94 phytochemicals were screened by a hybrid machine learning model constructed by combining 6 confirmatory bioassays against SARS-CoV-2 replication using an instance-based learner lazy k-nearest neighbour classifier. Further, 25 screened compounds with excellent drug-like properties were subjected to molecular docking. The phytochemical Cepharadione A from the plant Piper longum showed binding potential against four proteins with the highest binding energy of −10.90 kcal/mol. The compound has acceptable absorption, distribution, metabolism, excretion, and toxicity properties and exhibits stable binding behaviour in terms of root mean square deviation (0.068 ± 0.05 nm), root-mean-square fluctuation, hydrogen bonds, solvent accessible surface area (83.88–161.89 nm2), and molecular mechanics Poisson-Boltzmann surface area during molecular dynamics simulation of 200 ns with selected target proteins. Concerning the utility of natural compounds in the therapeutics formulation, Cepharadione A could be further investigated as a remarkable lead candidate for the development of therapeutic drugs against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

In silico design and identification of new peptides for mitigating hIAPP aggregation in type 2 diabetes

The aberrant misfolding and self-aggregation of human islet amyloid polypeptide (hIAPP or amylin) into cytotoxic aggregates are implicated in the pathogenesis of type 2 diabetes (T2D). Among various inhibitors, short peptides derived from the amyloidogenic regions of hIAPP have been employed as hIAPP aggregation inhibitors due to their low immunogenicity, biocompatibility, and high chemical diversity. Recently, hIAPP fragment HSSNN18-22 was identified as an amyloidogenic sequence and displayed higher antiproliferative activity to RIN-5F cells. Various hIAPP aggregation inhibitors have been designed by chemical modifications of the highly amyloidogenic sequence (NFGAIL) of hIAPP. In this work, a library of pentapeptides based on fragment HSSNN18-22 was designed and assessed for their efficacy in blocking hIAPP aggregation using an integrated computational screening approach. The binding free energy calculations by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method identified HSSQN and HSSNQ that bind to hIAPP monomer with a binding affinity of −21.25 ± 4.90 and −19.73 ± 3.10 kcal/mol, respectively, which is notably higher as compared to HSSNN (–11.90 ± 4.12 kcal/mol). The sampling of the non aggregation-prone helical conformation was notably increased from 23.5 ± 3.0 in the hIAPP monomer to 38.1 ± 3.6, and 33.8 ± 3.0% on the incorporation of HSSQN, and HSSNQ, respectively, which indicate reduced aggregation propensity of hIAPP monomer. The pentapeptides, HSSQN and HSSNQ, identified as hIAPP aggregation inhibitors in this work can be further conjugated with various metal chelating peptides to yield more efficacious and clinically relevant multifunctional modulators for targeting various pathological hallmarks of T2D.

Triamcinolone as a Potential Inhibitor of SARS-CoV-2 Main Protease and Cytokine Storm: An In silico Study

Background: An ongoing global public health concern is the emerging COVID-19 pandemic triggered by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mpro, a main protease of SARSCoV- 2, has been established as a potential drug target because of its direct role in viral replication and ability to infiltrate the multiple host pathways. Objective: This research aims to classify new therapeutic drug candidates who may be repositioned for COVID-19 therapeutics. Methods: We have taken similar drug compounds of Dexamethasone and targeted the main protease of SARS-CoV-2 (Mpro) along with the key molecules involved in the 'cytokine storm.' Further, we did MD simulations and calculated the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) on the active site of the main protease of SARS-CoV-2 (Mpro) and TNF-α, IL-6, & IL-1β to explore the binding affinity and stability. Results: Based on our study outcome, Triamcinolone emerged as the most promising inhibitor of the main protease of SARS-CoV-2 (Mpro) and the cytokine storm molecules, i.e., TNF-α, IL-6, and IL-1β. Conclusion: This research investigates the repositioning of COVID-19 drugs as a new therapeutic application.

In silico discovery of food-derived phytochemicals against asialoglycoprotein receptor 1 for treatment of hypercholesterolemia: Pharmacophore modeling, molecular docking and molecular dynamics simulation approach

Hypercholesterolemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Successful management of cholesterol metabolism disorders can prevent these ASCVD effectively. Asialoglycoprotein receptor 1 (ASGR1) is the main subtype of sialoglycoprotein receptor, which is specifically expressed in the liver and mediates the endocytosis of blood asialoglycoprotein to lysosome degradation. Recently, ASGR1 has been reported as a new therapeutic target for the treatment of hypercholesterolemia. In this study, the main aim was to identify natural ASGR1 inhibitors from plant food chemicals library through pharmacophore and docking based virtual screening. Total 14 phytochemicals of potential ASGR1 inhibitors were identified, which presented docking affinity higher than control compound through docking based virtual screening. The docking pose showed the top three hits interacted residues were located at active pocket of ASGR1 with hydrogen bonds, hydrophobic interactions and electrostatic interactions. The top three hits (ZINC85664954, ZINC169372863, and ZINC195764535) were then subjected to 200 ns molecular dynamics simulation to evaluate the stability of docked complexes. These results showed that selected phytochemicals bound to ASGR1 with higher stability than control compound. Binding free energy of each docked complex was calculated by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. The binding free energy of ZINC85664954, ZINC169372863, ZINC195764535, and control-ASGR1 docked complexes were −18.359, −13.303, −14.389, and −6.229 kcal/mol, respectively. This indicated that selected hits bound to ASGR1 with higher affinity than control compound. Network pharmacology analysis shows that these phytochemicals have obvious multiple-effects and can regulate various biochemical pathways related to hypercholesterolemia. Besides, selected phytochemicals have suitable pharmacokinetics properties, suggesting that these compounds may be potential drug candidates. This study may be contributed to rational design of novel ASGR1 inhibitors for treatment of hypercholesterolemia.

Computational insights into pediatric adenovirus inhibitors: in silico strategies for drug repurposing

Human adenovirus (HADV) infection can pose a serious threat to children, leading to a variety of respiratory illnesses and other complications. Particularly, children with weak immune systems are vulnerable to severe adenovirus infections with high mortality. The main focus of this study is to propose new antiviral agents as lead HADV inhibitors for children. So, several antiviral agents used in children were subjected to finding new HADV inhibitors using important computational methods of molecular docking, molecular dynamics (MD) simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations, density functional theory (DFT), and pharmacokinetic analysis. Molecular docking of standard cidofovir along with other ligands, suggested that sofosbuvir has the highest binding energy (−10.8 kcal/mol), followed by baloxavir marboxil (−10.36 kcal/mol). Further, the analysis of molecular interactions using MD simulation (100 ns) and MM-PBSA indicated that baloxavir marboxil has formed the most stable protein–ligand complex with HADV, followed by sofosbuvir. The binding free energies of baloxavir marboxil and sofosbuvir were found to be −61.724 kJ/mol and −48.123 kJ/mol, respectively. The DFT and drug-likeness properties of these compounds were also investigated. Overall, two antiviral agents, such as baloxavir marboxil, and sofosbuvir are suggested as lead repurposed candidates against HADV. Communicated by Ramaswamy H. Sarma