Molecular Dynamics Simulation Approach Research Articles

Unraveling the Influence of Nitration on Pore Formation Time in Electroporation of Cell Membranes: A Molecular Dynamics Simulation Approach

Abstract Electroporation, the transient permeabilization of cell membranes induced by electric fields, is an essential technique in biomedicine, facilitating gene delivery, drug transport, and cancer therapy. Despite its wide application, the influence of nitration, a biological modification involving the addition of nitro groups to phospholipids, on electroporation dynamics remains understudied. Here, we employ molecular dynamics simulations to investigate the impact of nitration on pore formation during electroporation. By systematically varying nitration levels and electric field strengths, we explore the nuanced interplay between nitration and electroporation kinetics. Our simulations reveal that increasing nitration levels significantly accelerate pore formation, with notable reductions in pore formation times observed at higher nitration percentages and stronger electric fields. This phenomenon underscores the modulatory role of nitration in altering the dynamics of electroporation. Additionally, our study sheds light on the intricate mechanisms underlying this process, providing essential insights for optimizing electroporation protocols in gene therapy, drug delivery, plasma cancer treatment and related biomedical applications. These findings illuminate the synergistic relationship between nitration and electroporation, paving the way for future advancements in this vital field.

Real-Time Ab Initio Investigation on Hot Electron Relaxation Dynamics in Silicon.

The relaxation of hot electrons in semiconductors is pivotal for both energy harvesting processes and optoelectronics. Utilizing a self-developed non-adiabatic molecular dynamics simulation approach in the momentum space (NAMD_k), we have examined the dynamics of hot electrons in silicon. Whether excited from the Γ or L point, the relaxation dynamics exhibit two distinct stages. Initially, within 100 fs, electrons scatter with phonons throughout the Brillouin zone. Subsequently, over a few picoseconds, they further relax toward the conduction band minimum as a whole. This picture of hot electron relaxation is highly consistent with the quasi-equilibrium hot electron ensemble (HEE) concept. Throughout the hot electron relaxation process, energy transfer to phonons is efficient, leading to time-dependent phonon excitation, which is thoroughly analyzed. This investigation provides a novel perspective on hot electron relaxation in silicon, which holds substantive implications for the realm of photovoltaic and optoelectronic device applications.

Truncated variants of thyroid hormone receptor beta display disease-inflicting malfunctioning at cellular level

Thyroid hormone receptor β (THRβ) is a member of the nuclear receptor superfamily of ligand-modulated transcription factors. Upon ligand binding, THRβ sequentially recruits the components of transcriptional machinery to modulate target gene expression. In addition to regulating diverse physiological processes, THRβ plays a crucial role in hypothalamus-pituitary-thyroid axis feedback regulation. Anomalies in THRβ gene/protein structure are associated with onset of diverse disease states. In this study, we investigated disease-inflicting truncated variants of THRβ using in-silico analysis and cell-based assays. We examined the THRβ truncated variants on multiple test parameters, including subcellular localization, ligand-receptor interactions, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions. Moreover, molecular dynamic simulation approaches predicted that shortened THRβ-LBD due to point mutations contributes proportionally to the loss of structural integrity and receptor stability. Deviant subcellular localization and compromised transcriptional function were apparent with these truncated variants. Present study shows that ‘mitotic bookmarking’ property of some THRβ variants is also affected. The study highlights that structural and conformational attributes of THRβ are necessary for normal receptor functioning, and any deviations may contribute to the underlying cause of the inflicted diseases. We anticipate that insights derived herein may contribute to improved mechanistic understanding to assess disease predisposition.

Mechanical and viscoelastic characterization of Al2O3 based polymer nanocomposites: An experimental and molecular dynamics simulation approach

Polymer nanocomposites (PNCs) being revolutionary materials, comprises polymer matrix phase and nanoparticles (NPs) phase. This study focuses on incorporating alumina (Al2O3) into poly-dimethyl siloxane (PDMS) matrix to analyze viscoelastic behavior and damping in response to dynamic mechanical loading. The experiments were performed using nano-DMA for comparing how Al2O3 reinforcement influences structural conformations and dynamic properties of PNCs. At 100 Hz, the storage modulus (E′) increases by 150%, 20%, and 74% for 1.0 wt% NPs with average particle sizes of 25 nm, 80 nm, and 200 nm, respectively. The significant changes in storage modulus and hardness values occur during variable frequencies (10 to 50 Hz) for 1.0 wt%, 9.0 wt%, and 7.0 wt% with reinforcements of 25 nm, 80 nm, and 200 nm, respectively. Adhesion factor and reinforcement efficiency factor highlight complementary effects of reinforcements at different frequencies. Further, an all-atom MD simulation method characterizes static and dynamic properties, predicting comprehensive dynamical and structural–property relationships. This quantifies damping capacity and reveals insights into how Al2O3 alters the material’s behavior. In summary, the study provides a precise comparative analysis of overall PNC performance, emphasizing the intrinsic effect on mechanical properties. It recognizes deformation mechanisms driving energy storage and dissipation for developing PNCs with enhanced mechanical performance.

Potential toxicity of graphene (oxide) quantum dots via directly covering the active site of anterior gradient homolog 2 protein

Graphene quantum dots (GQDs) have attracted significant attention in biomedicine, while extensive investigations have revealed a reverse regarding the potential biotoxicity of GQDs. In order to supplementing the understanding of the toxicity profile of GQDs, this study employs a molecular dynamics (MD) simulation approach to systematically investigate the potential toxicity of both GQDs and Graphene Oxide Quantum Dots (GOQDs) on the Anterior Gradient Homolog 2 (AGR2) protein, a key protein capable of protecting the intestine. We construct two typical simulation systems, in which an AGR2 protein is encircled by either GQDs or GOQDs. The MD results demonstrate that both GQDs and GOQDs can directly make contact with and even cover the active site (specifically, the Cys81 amino acid) of the AGR2 protein. This suggests that GQDs and GOQDs have the capability to inhibit or interfere with the normal biological interaction of the AGR2 active site with its target protein. Thus, GQDs and GOQDs exhibit potential detrimental effects on the AGR2 protein. Detailed analyses reveal that GQDs adhere to the Cys81 residue due to van der Waals (vdW) interaction forces, whereas GOQDs attach to the Cys81 residue through a combination of vdW (primary) and Coulomb (secondary) interactions. Furthermore, GQDs aggregation typically adsorb onto the AGR2 active site, while GOQDs adsorb to the active site of AGR2 one by one. Consequently, these findings shed new light on the potential adverse impact of GQDs and GOQDs on the AGR2 protein via directly covering the active site of AGR2, providing valuable molecular insights for the toxicity profile of GQD nanomaterials.

Simulation Study of Polyethylene Terephthalate Hydrolase Adsorption on Self-Assembled Monolayers.

Polyethylene terephthalate (PET) hydrolase, discovered in Ideonella sakaiensis (IsPETase), is a promising agent for the biodegradation of PET under mild reaction conditions, yet the thermal stability is poor. The efficient immobilization and orientation of IsPETase on different solid substrates are essential for its application. In this work, the combined parallel tempering Monte Carlo simulation with the all-atom molecular dynamics simulation approach was adopted to reveal the adsorption mechanism, orientation, and conformational changes of IsPETase adsorbed on charged self-assembled monolayers (SAMs), including COOH-SAM and NH2-SAM with different surface charge densities (SCDs). The results show that the protein adsorption orientation was determined not only by attraction interactions but also by repulsion interactions. IsPETase is adsorbed on the COOH-SAM surface with an "end-on" orientation, which favors the exposure of the catalyzed triplet to the solution. In addition, the entrance to the catalytic active center is larger on the COOH-SAM surface with a low SCD. This work reveals the controlled orientation and conformational information on IsPETase on charged surfaces at the atomistic level. This study would certainly promote our understanding of the mechanism of IsPETase adsorption and provide theoretical support for the design of substrates for IsPETase immobilization.

Deciphering ACE2-RBD binding affinity through peptide scanning: A molecular dynamics simulation approach

Rapid discovery of target information for protein-protein interactions (PPIs) is significant in drug design, diagnostics, vaccine development, antibody therapy, etc. Peptide microarray is an ideal tool for revealing epitope information of PPIs. In this work, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) and the host cell receptor angiotensin-converting enzyme 2 (ACE2) were introduced as a model to study the epitope information of RBD-specific binding to ACE2 via a combination of theoretical calculations and experimental validation. Through dock and molecular dynamics simulations, it was found that among the 22 peptide fragments that consist of RBD, #14 (YNYLYRLFRKSNLKP) has the highest binding strength. Subsequently, the experiments of peptide microarray constructed based on plasmonic materials chip also confirmed the theoretical calculation data. Compared to other methods, such as phage display technology and surface plasmon resonance (SPR), this method is rapid and cost-effective, providing insights into the investigation of pathogen invasion processes and the timely development of peptide drugs and other fields.

An assessment of crucial structural contributors of HDAC6 inhibitors through fragment-based non-linear pattern recognition and molecular dynamics simulation approaches

Amidst the Zn2+-dependant isoforms of the HDAC family, HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett’s Syndrome, Alzheimer’s disease, Huntington’s disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases. In this context, this study has been carried out to evaluate the potential structural contributors of quinazoline-cap-containing HDAC6 inhibitors via machine learning (ML), conventional classification-dependant QSAR, and MD simulation-based binding mode of interaction analysis toward HDAC6 binding. This combined conventional and modern molecular modeling study has revealed the significance of the quinazoline moiety, substitutions present at the quinazoline cap group, as well as the importance of molecular property, number of hydrogen bond donor-acceptor functions, carbon-chlorine distance that significantly affects the HDAC6 binding of these inhibitors, subsequently affecting their potency . Interestingly, the study also revealed that the substitutions such as the chloroethyl group, and bulky quinazolinyl cap group can affect the binding of the cap function with the amino acid residues present in the loops proximal to the catalytic site of HDAC6. Such contributions of cap groups can lead to both stabilization and destabilization of the cap function after occupying the hydrophobic catalytic site by the aryl hydroxamate linker-ZBG functions.

Examination of Couette Flow with a Pressure Gradient and Heat Conduction Using Molecular Dynamics Simulation

As computer capabilities improve, Molecular Dynamics simulations are becoming more important for solving various flow problems. In this study, Couette and Poiseuille flows at different wall temperatures were investigated using a hard-sphere Molecular Dynamics simulation approach. Although a low spacing ratio was used in the simulations, the results are valid for rarefied gas flows when proper scaling based on the Knudsen number was used because only binary collisions with a hard-sphere model were considered. The main focus of this study was the examination of the effects of various wall speeds, pressure gradients, and wall temperatures. A pressure gradient was generated by developing a modified selective periodicity condition in the flow direction. With the combined effect of the pressure gradient and the wall velocities, subsonic, transonic, and supersonic speeds in nanochannels were examined. With the combination of different parameters, 1260 simulation cases were conducted. The results showed that there are temperature and velocity slips that are dependent on not only the temperature and velocity values but also on the magnitudes of a pressure gradient. The pressure gradient also caused nonlinearities in temperature and velocity profiles.

Integrating virtual screening, pharmacoinformatics profiling, and molecular dynamics: identification of promising inhibitors targeting 3CLpro of SARS-CoV-2.

Introduction: The pursuit of effective therapeutic solutions for SARS-CoV-2 infections and COVID-19 necessitates the repurposing of existing compounds. This study focuses on the detailed examination of the central protease, 3-chymotrypsin-like protease (3CLpro), a pivotal player in virus replication. The combined approach of molecular dynamics simulations and virtual screening is employed to identify potential inhibitors targeting 3CLpro. Methods: A comprehensive virtual screening of 7120 compounds sourced from diverse databases was conducted. Four promising inhibitors, namely EN1036, F6548-4084, F6548-1613, and PUBT44123754, were identified. These compounds exhibited notable attributes, including high binding affinity (ranging from -5.003 to -5.772Kcal/mol) and superior Induced Fit Docking scores (ranging from -671.66 to -675.26Kcal/mol) compared to co-crystallized ligands. Results: In-depth analysis revealed that F6548-1613 stood out, demonstrating stable hydrogen bonds with amino acids His41 and Thr62. Notably, F6548-1613 recorded a binding energy of -65.72kcal/mol in Molecular Mechanics Generalized Born Surface Area (MMGBSA) simulations. These findings were supported by Molecular Dynamics simulations, highlighting the compound's efficacy in inhibiting 3CLpro. Discussion: The identified compounds, in compliance with Lipinski's rule of five and exhibiting functional molecular interactions with 3CLpro, present promising therapeutic prospects. The integration of in silico methodologies significantly expedites drug discovery, laying the foundation for subsequent experimental validation and optimization. This approach holds the potential to develop effective therapeutics for SARS-CoV-2.

Role of Protonation States in the Stability of Molecular Dynamics Simulations of High-Resolution Membrane Protein Structures.

Classical molecular dynamics (MD) simulations provide unmatched spatial and time resolution of protein structure and function. However, the accuracy of MD simulations often depends on the quality of force field parameters and the time scale of sampling. Another limitation of conventional MD simulations is that the protonation states of titratable amino acid residues remain fixed during simulations, even though protonation state changes coupled to conformational dynamics are central to protein function. Due to the uncertainty in selecting protonation states, classical MD simulations are sometimes performed with all amino acids modeled in their standard charged states at pH 7. Here, we performed and analyzed classical MD simulations on high-resolution cryo-EM structures of two large membrane proteins that transfer protons by catalyzing protonation/deprotonation reactions. In simulations performed with titratable amino acids modeled in their standard protonation (charged) states, the structure diverges far from its starting conformation. In comparison, MD simulations performed with predetermined protonation states of amino acid residues reproduce the structural conformation, protein hydration, and protein-water and protein-protein interactions of the structure much better. The results support the notion that it is crucial to perform basic protonation state calculations, especially on structures where protonation changes play an important functional role, prior to the launch of any conventional MD simulations. Furthermore, the combined approach of fast protonation state prediction and MD simulations can provide valuable information about the charge states of amino acids in the cryo-EM sample. Even though accurate prediction of protonation states in proteinaceous environments currently remains a challenge, we introduce an approach of combining pKa prediction with cryo-EM density map analysis that helps in improving not only the protonation state predictions but also the atomic modeling of density data.

Evaluation of binding mechanism of dietary phytochemical, capsaicin, with human transferrin: targeting neurodegenerative diseases therapeutics.

Human transferrin (htf) plays a crucial role in regulating the balance of iron within brain cells; any disruption directly contributes to the development of Neurodegenerative Diseases (NDs) and other related pathologies, especially Alzheimer's Disease (AD). In recent times, a transition towards natural compounds is evident to treat diseases and this shift is mainly attributed to their broad therapeutic potential along with minimal side effects. Capsaicin, a natural compound abundantly found in red and chili peppers, possess neuroprotective potential. The current work targets to decipher the interaction mechanism of capsaicin with htf using experimental and computational approaches. Molecular docking analysis revealed that capsaicin occupies the iron binding pocket of htf, with good binding affinity. Further, the binding mechanism was investigated atomistically using Molecular dynamic (MD) simulation approach. The results revealed no significant alterations in the structure of htf implying the stability of the complex. In silico observations were validated by fluorescence binding assay. Capsaicin binds to htf with a binding constant (K) of 3.99 × 106M-1, implying the stability of the htf-capsaicin complex. This study lays a platform for potential applications of capsaicin in treatment of NDs in terms of iron homeostasis.

Structural insights into non-hotspot KRAS mutations and their potential as targets for effective cancer therapies

Kirsten rat sarcoma virus protein (KRAS) is a protein that plays a central role in signal transduction using extracellular signal regulated kinase (ERK) and mitogen activated protein kinase (MAPK) cellular signaling pathway. KRAS is a frequently mutated oncogene and plays a pivotal role in tumor initiation and progression. Hotspot mutations on codon 12, 13 and 61 in KRAS are well-known for their role in drug resistance and non-hotspot mutations also play a significant part in contributing to resistance mechanisms. The understanding of how these non-hotspot mutations might affect the signal transduction of KRAS and their contribution towards drug resistance is understudied. Here we provide structural insights into the interaction of non-hotspot KRAS mutants with GTP (the native ligand) using a molecular docking and molecular dynamics simulation approach. Extensive molecular docking and simulation studies suggest that non-hotspot mutations (E31D and E63K) show stable interaction with native ligand using all five trajectories, as evidenced by root mean square of distance (RMSD), root mean square of fluctuation (RMSF), radius of gyration (RoG), coulomb short-range energy and MMGBSA analysis. These results suggest that non-hotspot mutations do not undermine the oncogenic nature of KRAS. This observation is consistent with previous findings where overexpressing E31D and E63K mutations share phenotypic features with G12D and G13D transfected cells, including increased proliferative capacity, actin cytoskeleton organization, and migration rates. We further test whether FDA-approved KRAS inhibitors sotorasib and adagrasib successfully inhibit the E31D and E63K mutants. Results suggest that these two non-hotspot mutants can be inhibited by both drugs with following trend of structural stability (E31D > E63K > wild-KRAS > Q61H > G12C). Based on sharp coherence in trajectories between wild KRAS and non-hotspot mutants, it is suggested that these novel mutants do not contribute to drug resistance mechanism. Overall, we provide a comprehensive understanding of the impact of non-hotspot mutations on KRAS and their potential as targets for effective cancer therapies. Communicated by Ramaswamy H. Sarma

Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations.

Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved through cycles in which Hsp90 and Hsp70, regulated by task-specific co-chaperones, process ATP and become part of a complex network that undergoes extensive compositional and conformational variations. Despite impressive advances in structural knowledge, the mechanisms that regulate the dynamics of functional assemblies, their response to nucleotides, and their relevance for client remodeling are still elusive. Here, we focus on the glucocorticoid receptor (GR):Hsp90:Hsp70:co-chaperone Hop client-loading and the GR:Hsp90:co-chaperone p23 client-maturation complexes, key assemblies in the folding cycle of glucocorticoid receptor (GR), a client strictly dependent upon Hsp90/Hsp70 for activity. Using a combination of molecular dynamics simulation approaches, we unveil with unprecedented detail the mechanisms that underpin function in these chaperone machineries. Specifically, we dissect the processes by which the nucleotide-encoded message is relayed to the client and how the distinct partners of the assemblies cooperate to (pre)organize partially folded GR during Loading and Maturation. We show how different ligand states determine distinct dynamic profiles for the functional interfaces defining the interactions in the complexes and modulate their overall flexibility to facilitate progress along the chaperone cycle. Finally, we also show that the GR regions engaged by the chaperone machinery display peculiar energetic signatures in the folded state, which enhance the probability of partial unfolding fluctuations. From these results, we propose a model where a dynamic cross-talk emerges between the chaperone dynamics states and remodeling of client-interacting regions. This factor, coupled to the highly dynamic nature of the assemblies and the conformational heterogeneity of their interactions, provides the basis for regulating the functions of distinct assemblies during the chaperoning cycle.

Raman spectroscopy study of 7,8-dihydrofolate inhibition on the Wuhan strain SARS-CoV-2 binding to human ACE2 receptor

Emerging evidence suggests that elevated levels of folic acid in the bloodstream may confer protection against Wuhan-SARS-CoV-2 infection and mitigate its associated symptoms. Notably, two comprehensive studies of COVID-19 patients in Israel and UK uncovered a remarkable trend, wherein individuals with heightened folic acid levels exhibited only mild symptoms and necessitated no ventilatory support. In parallel, research has underscored the potential connection between decreased folic acid levels and the severity of Covid-19 among hospitalized patients. Yet, the underlying mechanisms governing this intriguing inhibition remain elusive. In a quest to elucidate these mechanisms, we conducted a molecular dynamics simulation approach followed by a Raman spectroscopy study to delve into the intricate interplay between the folic acid metabolite, 7,8-dihydrofolate (DHF), and the angiotensin-converting enzyme ACE2 receptor, coupled with its interaction with the receptor-binding domain (RBD) of the Wuhan strain of SARS-CoV-2. Through a meticulous exploration, we scrutinized the transformation of the ACE2 + RBD complex, allowing these reactants to form bonds. This was juxtaposed with a similar investigation where ACE2 was initially permitted to react with DHF, followed by the exposure of the ACE2 + DHF complex to RBD. We find that DHF, when bonded to ACE2, functions as a physical barrier, effectively inhibiting the binding of the Wuhan strain RBD. This physicochemical process offers a cogent explanation for the observed inhibition of host cell infection in subjects receiving supplementary folic acid doses, as epidemiologically substantiated in multiple studies. This study not only sheds light on a potential avenue for mitigating SARS-CoV-2 infection but also underscores the crucial role of folic acid metabolites in host-virus interactions. This research paves the way for novel therapeutic strategies in the battle against COVID-19 and reinforces the significance of investigating the molecular mechanisms underlying the protective effects of folic acid in the context of viral infections.

Magnesium Ion Gated Ion Rejection through Carboxylated Graphene Oxide Nanopore: A Theoretical Study.

While nanoporous graphene oxide (GO) is recognized as one of the most promising reverse osmosis desalination membranes, limited attention has been paid to controlling desalination performance through the large GO pores, primarily due to significant ion leakage resulting in the suboptimal performance of these pores. In this study, we employed a molecular dynamics simulation approach to demonstrate that Mg2+ ions, adhered to carboxylated GO nanopores, can function as gates, regulating the transport of ions (Na+ and Cl-) through the porous GO membrane. Specifically, the presence of divalent cations near a nanopore reduces the concentration of salt ions in the vicinity of the pore and prolongs their permeation time across the pore. This subsequently leads to a notable enhancement in salt rejection rates. Additionally, the ion rejection rate increases with more adsorbed Mg2+ ions. However, the presence of the adsorbed Mg2+ ions compromises water transport. Here, we also elucidate the impact of graphene oxidation degree on desalination. Furthermore, we design an optimal combination of adsorbed Mg2+ ion quantity and oxidation degree to achieve high water flux and salt rejection rates. This work provides valuable insights for developing new nanoporous graphene oxide membranes for controlled water desalination.

Multiscale Molecular Dynamics Simulations of an Active Self-Assembling Material.

Inspired by the adaptability observed in biological materials, self-assembly processes have attracted significant interest for their potential to yield novel materials with unique properties. However, experimental methods have often fallen short in capturing the molecular details of the assembly process. In this study, we employ a multiscale molecular dynamics simulation approach, complemented by NMR quantification, to investigate the mechanism of self-assembly in a redox-fueled bioinspired system. Contrary to conventional assumptions, we have uncovered a significant role played by the monomer precursor in the assembly process, with its presence varying with concentration and the extent of conversion of the monomer to the dimer. Experimental confirmation through NMR quantification underscores the concentration-dependent incorporation of monomers into the fibrous structures. Furthermore, our simulations also shed light on the diverse intermolecular interactions, including T-shaped and parallel π stacking, as well as hydrogen bonds, in stabilizing the aggregates. Overall, the open conformation of the dimer is preferred within these aggregates. However, inside the aggregates, the distribution of conformations shifts slightly to the closed conformation compared to on the surface. These findings contribute to the growing field of bioinspired materials science by providing valuable mechanistic and structural insights to guide the design and development of self-assembling materials with biomimetic functionalities.

In silico exploration of the potential inhibitory activities of in-house and ZINC database lead compounds against alpha-glucosidase using structure-based virtual screening and molecular dynamics simulation approach

Inhibitors of α-glucosidase have been used to treat type-2 diabetes (T2DM) by preventing the breakdown of carbohydrates into glucose and prevent enhancing glucose conversion. Structure-based virtual screening (SBVS) was used to generate novel chemical scaffold-ligand α-glucosidase inhibitors. The databases were screened against the receptor α-glucosidase using SBVS and molecular dynamics simulation (MDS) techniques in this study. Based on molecular docking studies, three and two compounds of α-glucosidase inhibitors were chosen from a commercial database (ZINC) and an In-house database for this study respectively. The mode of binding interactions of the selected compounds later predicted their α-glucosidase inhibitory potential. Finally, one out of three lead compound from ZINC and one out of two lead compound from In-house database were shortlisted based on interactions. Furthermore, MDS and post-MDS strategies were used to refine and validate the shortlisted leads along with the reference acarbose/α-glucosidase. The Hits’ ability to inhibit α-glucosidase was predicted by SBVS, indicating that these compounds have good inhibitory activities. The lead inhibitor’s structure may serve as templates for the design of novel inhibitors, and in vitro testing to confirm their anti-diabetic potential is necessary. These insights can help rationally design new effective anti-diabetic drugs. Communicated by Ramaswamy H. Sarma

Secondary metabolites of Trichoderma spp. as EGFR tyrosine kinase inhibitors: Evaluation of anticancer efficacy through computational approach.

The present study explores the epidermal growth factor receptor (EGFR) tyrosine kinase inhibition efficacy of secondary metabolites in Trichoderma spp. through molecular docking, molecular dynamics (MD) simulation and MM-PBSA approach. The result of molecular docking confirmed that out of 200 metabolites screened, three metabolites such as Harzianelactone A, Pretrichodermamide G and Aspochalasin M, potentially bound with the active binding site of EGFR tyrosine kinase domain(PDB ID: 1M17) with a threshold docking score of ≤- 9.0 kcal/mol when compared with the standard EGFR inhibitor (Erlotinib). The MD simulation was run to investigate the potential for stable complex formation in EGFR tyrosine kinase domain-unbound/lead metabolite (Aspochalasin M)-bound/standard inhibitor (Erlotinib)-bound complex. The MD simulation analysis at 100 ns revealed that Aspochalasin M formed the stable complex with EGFR. Besides, the in silico predication of pharmacokinetic properties further confirmed that Aspochalasin M qualified the drug-likeness rules with no harmful side effects (viz., hERG toxicity, hepatotoxicity and skin sensitization), non-mutagenicity and favourable logBB value. Moreover, the BOILED-Egg model predicted that Aspochalasin M showed a higher gastrointestinal absorption with improved bioavailability when administered orally and removed from the central nervous system (CNS). The results of the computational studies concluded that Aspochalasin M possessed significant efficacy in binding EGFR's active sites compared to the known standard inhibitor (Erlotinib). Therefore, Aspochalasin M can be used as a possible anticancer drug candidate and further in vitro and in vivo experimental validation of Aspochalasin M of Trichoderma spp. are required to determine its anticancer potential.

Identification of antiviral phytochemicals from cranberry as potential inhibitors of SARS-CoV-2 main protease (Mpro)

Cranberry phytochemicals are known to possess antiviral activities. In the current study, we explored the therapeutic potential of cranberry against SARS-CoV-2 by targeting its main protease (Mpro) enzyme. Firstly, phytochemicals of cranberry origin were identified from three independent databases. Subsequently, virtual screening, using molecular docking and molecular dynamics simulation approaches, led to the identification of three lead phytochemicals namely, cyanidin 3-O-galactoside, β-carotene and epicatechin. Furthermore, in vitro enzymatic assays revealed that cyanidin 3-O-galactoside had the highest inhibitory potential with IC50 of 9.98 μM compared to the other two phytochemicals. Cyanidin 3-O-galactoside belongs to the class of anthocyanins. Anthocyanins extracted from frozen cranberry also exhibited the highest inhibitory potential with IC50 of 23.58 μg/ml compared to the extracts of carotenoids and flavanols, the class for β-carotene and epicatechin, respectively. Finally, we confirm the presence of the phytochemicals in the cranberry extracts using targeted LC-MS/MS analysis. Our results, therefore, indicate that the identified cranberry-derived bioactive compounds as well as cranberry could be used for therapeutic interventions against SARS-CoV-2.