In silico evaluation of the downstream effect of mutated glucagon is consistent with higher blood glucose homeostasis in Galliformes and Strigiformes.

In contrast to mammals, glucagon is reported as a much more potent blood glucose modulator in birds. Interestingly, we have found p.Thr16Ser mutation, a variation in the highly conserved glucagon hormone, in Galliformes as well as Strigiformes. To check the effect of this mutation on the receptor binding of glucagon, we predicted the ancestral glucagon receptor sequence of all available Galliformes and Strigiformes species. Subsequently, we analysed their binding to the mutated and wild type glucagon (ancestral) by molecular dynamics simulation. At first, we made a model of ancestral glucagon receptor and ancestral mutated, and wild type glucagon in the order Galliformes and Strigiformes. Then we performed molecular dynamics for each Galliformes and Strigiformes receptor as well as each glucagon peptide, respectively. The final structures were used for docking simulation of glucagon to their receptors. The results of the docking simulations showed a stronger binding affinity of mutated glucagon to glucagon receptors. Afterward, we obtained blood glucose concentrations of all available Galliformes members, as well as all available members of its only taxonomic neighbour (order Anseriformes) in superorder Galloanserae. Interestingly the p.Thr16Ser mutation could finely cluster these two orders into two groups: higher blood glucose concentration (order Galliformes, 17.64 ± 1.66 mMol/L) and lower blood glucose concentration (order Anseriformes, 11.34 ± 1.11 mMol/L). Strigiformes which carry the mutated glucagon peptide show also high blood glucose concentrations (17.40 ± 1.51 mMol/L). Therefore, the results suggest this mutation, which leads to stronger binding affinity of mutated glucagon to its receptor, may be a driving force for higher blood glucose homeostasis in the related birds.

In silico and in vitro effects of the I30T mutation on myelin protein zero instability in the cell membrane.

Charcot-Marie-Tooth (CMT) diseases are a heterogeneous group of genetic peripheral neuropathies caused by mutations in a variety of genes, which are involved in the development and maintenance of peripheral nerves. Myelin protein zero (MPZ) is expressed by Schwann cells, and MPZ mutations can lead to primarily demyelinating polyneuropathies including CMT type 1B. Different mutations demonstrate various forms of disease pathomechanisms, which may be beneficial in understanding the disease cellular pathology. Our molecular dynamics simulation study on the possible impacts of I30T mutation on the MPZ protein structure suggested a higher hydrophobicity and thus lower stability in the membranous structures. A study was also conducted to predict native/mutant MPZ interactions. To validate the results of the simulation study, the native and mutant forms of the MPZ protein were separately expressed in a cellular model, and the protein trafficking was chased down in a time course pattern. In vitro studies provided more evidence on the instability of the MPZ protein due to the mutation. In this study, qualitative and quantitative approaches were adopted to confirm the instability of mutant MPZ in cellular membranes.

Cycloarta-23-ene-3beta,25-diol a pentacyclic steroid from Euphorbia spinidens, as COX inhibitor with molecular docking, and in vivo study of its analgesic and anti-inflammatory activities in male swiss mice and wistar rats.

BACKGROUND AND AIMS: Euphorbia is a large genus of flowering plants. In Iran, some plants of this family have been used in the treatment of inflammatory disorders and also to relieve back pain. Euphorbia spinidens is a rich source of Cycloarta-23-ene-3beta,25-diol. Cycloartane structures are the starting material for the synthesis of plant steroids, and the aim of this study is to demonstrate COX inhibitory activity, molecular docking and in vivo approach of anti-inflammatory activity of cycloartane compound isolated from Euphorbia spinidens. MATERIAL AND METHODS: Plant material was extracted with acetone-chloroform and submitted to column chromatography for fractionation. Based on preliminary 1H-NMR spectra, cycloartane fraction was selected and purified by repeated recycle HPLC system. The structure and purity of compound were determined by 1H and 13C-NMR, HPTLC, and mass spectra. Inhibitory activities of the tested compounds on COX-1 and COX-2 were evaluated by a colorimetric COX (ovine) inhibitor screening method. Vero cells were used to assess the toxicity against the normal cells, and calculate the selectivity index. COX inhibitory activity results were evaluated and confirmed by molecular docking experiments. In the in vivo approach, analgesic activity was assessed by acetic acid-induced abdominal writhing and formalin tests. Croton oil-induced ear edema in mice and carrageenan-induced rat paw edema in rats were used to evaluate anti-inflammatory activity. Pain tests were carried out on male Swiss mice (25-35 g). Male Wistar rats (160-200 g) were used for the carrageenan test. RESULTS: Cycloart-23-ene-3ß,25-diol showedin vitro cyclooxygenase 1 and 2 inhibitory activities with more selectivity for COX-2. Molecular docking by predicting binding energies in COX protein receptors confirmed in vitro COX inhibitory results, and determined the best position for ligand in COX receptors along with its residue interactions in receptor pockets, which must be considered for designing of their inhibitors. In the in vivo studies, cycloartane inhibited significantly acetic acid-induced abdominal contractions and formalin-induced licking behavior at a dose of 200 mg/kg. The same dose reduced croton oil ear edema in mice and carrageenan-induced paw edema in rats. CONCLUSION: Therefore, according to these findings, cycloart-23-ene-3beta,25-diol showed promising analgesic and anti-inflammatory effects with low toxicity against normal cells and can be suggested as a template lead for designing anti-inflammatory compounds with good selectivity index, and potency for COX-2 inhibitory activity.

The c.305del3 in IL-2 gene in Homonoidea theoretically affects IL-2/IL-2Rα interaction as well as lymphocyte homeostasis.

Interleukin-2 (IL-2) is a well-known monomeric T-cell growth factor that is produced primarily by activated CD4+ T cells following exposure to antigen. IL-2 structural analysis among primates showed a few polymorphisms as well as a 3-nucleotide deletion (c.305del3) in Hominoidea superfamily including Homo sapiens. On the other hand, the interaction of IL-2 with its alpha subunit of the receptor (IL-2Rα) is the first step for assembly of the whole IL-2R and considered as a species-specific phase. Four models of human IL-2, IL-2Rα, and their ancestral forms were made and were used for molecular dynamics (MD) simulation. Subsequently, the final structures were docked to each other and finally, the complexes were used for MD simulation. Our results showed that the above mentioned deletion led to weaker interaction of human IL-2 to its receptor relative toancestral IL-2. Association study of lymphocyte counts, as an indicator of IL-2 function, in 78 primate species with or without this deletion showed significant association of this deletion with their overall lymphocyte counts (P < .01). Therefore, it can be suggested that p.81delThr in IL-2 in Hominides superfamily interfered with interaction of IL-2 and IL-2Rα and led to overall decrease in lymphocyte counts in this superfamily of primates in comparison with other primates.

A theoretical and experimental study of calcium, iron, zinc, cadmium, and sodium ions absorption by aspartame.

Aspartame (L-Aspartyl-L-phenylalanine methyl ester) is a sweet dipeptide used in some foods and beverages. Experimental studies show that aspartame causes osteoporosis and some illnesses, which are similar to those of copper and calcium deficiency. This raises the issue that aspartame in food may interact with cations and excrete them from the body. This study aimed to study aspartame interaction with calcium, zinc, iron, sodium, and cadmium ions via molecular dynamics simulation (MD) and spectroscopy. Following a 480-ns molecular dynamics simulation, it became clear that the aspartame is able to sequester Fe2+, Ca2+, Cd2+, and Zn2+ ions for a long time. Complexation led to increasing UV-Vis absorption spectra and emission spectra of the complexes. This study suggests a potential risk of cationic absorption of aspartame. This study suggests that purification of cadmium-polluted water by aspartame needs a more general risk assessment.

Elucidation of Molecular Mechanisms Behind the Self-Assembly Behavior of Chitosan Amphiphilic Derivatives Through Experiment and Molecular Modeling.

PURPOSE: Chitosan-based polymeric micelles (CBPMs) are considered as promising carriers for delivery of anticancer drugs, imaging agents and genes. To optimize the physicochemical, pharmaceutical and biological properties of CBPMs, the molecular mechanisms behind the self-assembly behavior of chitosan (CHI) amphiphilic derivatives are elucidated. METHODS: This study has two stages. In the experimental stage, dexamethasone (DEX) as a hydrophobic group is grafted to CHI in three degrees of substitution in order to obtain CHI derivatives with different degrees of hydrophobicity. These new CHI amphiphilic derivatives (CHI_DEXs) form micelles in water where their critical aggregation concentration (CAC), size and zeta potential are measured. Through comparing the results of these measurements, the change of self-assembly behavior of CHI_DEXs in response to increasing their hydrophobicity is evaluated. Correlating this evaluation with the results of the 13 MD simulations conducted on CHI_DEXs in atomistic molecular dynamics (MD) simulation stage, reveals the molecular mechanisms behind the self-assembly behavior of CHI_DEXs. RESULTS: Our evaluation of the experimental results reveals that increasing hydrophobicity of a CHI amphiphilic derivative would not necessarily cause it to form micelles with lower CAC value, smaller size and lower zeta potential. The MD simulations reveal that there exists a balance between intra- and inter-chain interactions which is responsible for the self-assembly behavior of CHI amphiphilic derivatives. CONCLUSION: An increase in DS of the hydrophobic group triggers a cascade of molecular events that shifts the balance between intra- and inter-chain interactions leading to changes in the CAC, size and zeta potential of the CBPMs.

Dihydropyrimidine derivatives as MDM2 inhibitors.

One of the chief pathways to regulate p53 levels is MDM2 protein, which negatively controls p53 by direct inhibition. Many cancers overproduce MDM2 protein to interrupt p53 functions. Therefore, impeding MDM2's binding to p53 can reactivate p53 in tumor cells may suggest an effective approach for tumor therapy. Here, some Monastrol derivatives were designed in silico as MDM2 inhibitors, and their initial cytotoxicity was evaluated in vitro on MFC-7 and MDA-MB-231 cells. A small library of Monastrol derivatives was created, and virtual screening (VS) was performed on them. The first-ranked compound, which was extracted from VS, and the other six compounds 5a-5f were selected to carry out the single-docking and docking with explicit waters. The compound with the best average results was then subjected to molecular dynamic (MD) simulation. Compounds 5a-5f were chemically synthesized and evaluated in vitro for their initial cytotoxicity on MFC-7 and MDA-MB-231 cells by MTT assay. The best compound was compound 5d with ΔGave = -10.35 kcal/mol. MD simulation revealed a median potency in comparison with Nutlin-3a. The MTT assay confirmed the docking and MD experiments. 5d has an IC50 of 60.09 µM on MCF-7 cells. We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future.

In-silico study MM/GBSA binding free energy and molecular dynamics simulation of some designed remdesivir derivatives as the inhibitory potential of SARS-CoV-2 main protease.

Background and purpose: Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed. Experimental approach: The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study. Findings/Results: The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 A, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding. Conclusion and implications: Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

Lysine ε-aminolysis and incorporation of sulfhydryl groups into human brain tau 4R/1N and 306VQIVYK311 enhances the formation of beta structures and toxicity.

In the present study, we investigated the effects of N-homocysteine thiolactone (tHcy) modification on expressed and purified tau protein and the synthesized VQIVYK target peptide. The modified constructs were subjected to comprehensive validation using various methodologies, including mass spectrometry. Subsequently, in vivo, in vitro, and in silico characterizations were performed under both reducing and non-reducing conditions, as well as in the presence and absence of heparin as a cofactor. Our results unequivocally confirmed that under reducing conditions and in the presence of heparin, the modified constructs exhibited a greater propensity for aggregation. This enhanced aggregative behavior can be attributed to the disruption of lysine positive charges and the subsequent influence of hydrophobic and p-stacking intermolecular forces. Notably, the modified oligomeric species induced apoptosis in the SH-SY5Y cell line, and this effect was further exacerbated with longer incubation times and higher concentrations of the modifier. These observations suggest a potential mechanism involving reactive oxygen species (ROS). To gain a deeper understanding of the molecular mechanisms underlying the neurotoxic effects, further investigations are warranted. Elucidating these mechanisms will contribute to the development of more effective strategies to counteract aggregation and mitigate neurodegeneration.

A theoretical survey to find potential natural compound for inhibition of binding the RBD domain to ACE2 receptor based on plant antivirals.

The spike protein of coronavirus is crucial in binding and arrival of the virus to the human cell via binding to the human ACE2 receptor. In this study, at first 25 antiviral phytochemicals were docked into the RBD domain of spike protein, and then all complexes and free RBD domains were separately subjected to molecular dynamics simulation for 100 ns and MM/PBSA binding free energy calculation. In this phase, four ligands were chosen as hit compounds and a natural compound database (NPASS) was screened based on high similarity with these ligands, and 367 ligands were found. Then the same previous procedure was repeated for these ligands and ADME properties were investigated. Finally, virtual screening and 4400 ns MD simulation and MM/PBSA calculation revealed that new ligands including NPC67959, NPC157855, NPC248793, and NPC216361 can inhibit the RBD domain of spike protein and we propose them as potential drugs for experimental studies.Communicated by Ramaswamy H. Sarma.

Evolutionary trajectories of beta-lactamase NDM and DLST cluster in Pseudomonas aeruginosa: finding the putative ancestor.

Pseudomonas aeruginosa has different antibiotic resistance pathways, such as broad-spectrum lactamases and metallo-ß-lactamases (MBL), penicillin-binding protein (PBP) alteration, and active efflux pumps. Polymerase chain reaction (PCR) and sequencing methods were applied for double-locus sequence typing (DLST) and New Delhi metallo-ß-lactamase (NDM) typing. We deduced the evolutionary pathways for DLST and NDM genes of P. aeruginosa using phylogenetic network. Among the analyzed isolates, 62.50% of the P. aeruginosa isolates were phenotypically carbapenem resistance (CARBR) isolates. Characterization of isolates revealed that the prevalence of blaNDM, blaVIM, blaIMP, undetermined carbapenemase, and MexAB-OprM were 27.5%, 2%, 2.5%, 12.5%, and 15%, respectively. The three largest clusters found were DLST t20-105, DLST t32-39, and DLST t32-52. The network phylogenic tree revealed that DLST t26-46 was a hypothetical ancestor for other DLSTs, and NDM-1 was as a hypothetical ancestor for NDMs. The combination of the NDM and DLST phylogenic trees revealed that DLST t32-39 and DLST tN2-N3 with NDM-4 potentially derived from DLST t26-46 along with NDM-1. Similarly, DLST t5-91 with NDM-5 diversified from DLST tN2-N3 with NDM-4. This is the first study in which DLST and NDM evolutionary routes were performed to investigate the origin of P. aeruginosa isolates. Our study showed that the utilization of medical equipment common to two centers, staff members common to two centers, limitations in treatment options, and prescription of unnecessary high levels of meropenem are the main agents that generate new types of resistant bacteria and spread resistance among hospitals.

Preparing a database of corrected protein structures important in cell signaling pathways.

Background and purpose: Precise structures of macromolecules are important for structure-based drug design. Due to the limited resolution of some structures obtained from X-ray diffraction crystallography, differentiation between the NH and O atoms can be difficult. Sometimes a number of amino acids are missing from the protein structure. In this research, we intend to introduce a small database that we have prepared for providing the corrected 3D structure files of proteins frequently used in structure-based drug design protocols. Experimental approach: 3454 soluble proteins belonging to the cancer signaling pathways were collected from the PDB database from which a dataset of 1001 was obtained. All were subjected to corrections in the protein preparation step. 896 protein structures out of 1001 were corrected successfully and the decision on the remained 105 proposed twelve for homology modeling to correct the missing residues. Three of them were subjected to molecular dynamics simulation for 30 ns. Findings / Results: 896 corrected proteins were perfect and homology modeling on 12 proteins with missing residues in the backbone resulted in acceptable models according to Ramachandran, z-score, and DOPE energy plots. RMSD, RMSF, and Rg values verified the stability of the models after 30 ns molecular dynamics simulation. Conclusion and implication: A collection of 1001 proteins were modified for some defects such as adjustment of the bond orders and formal charges, and addition of missing side chains of residues. Homology modeling corrected the amino missing backbone residues. This database will be completed for quite a lot of water-soluble proteins to be uploaded to the internet.

One-pot synthesis of polyhydroquinoline-1,2,3-triazole hybrids in deep eutectic solvent as anti-leishmanial agents and molecular modeling studies.

The novel hybrids with 1,2,3-triazole and polyhydroquinoline scaffolds were successfully synthesized by multicomponent reaction of propargyloxybenzaldehyde, 1,3-cyclohexadione, ethylacetoacetate and ammonium acetate followed through click reaction in the presence of deep eutectic solvent ChCl/ZnCl2 as an efficient catalyst. Their anti-leishmanial activity was evaluated against amastigote and promastigote forms of L. tropica, L. major, and two different species of L. infantum. Furthermore, to determine the cytotoxicity of the hybrids, they were evaluated against the murine macrophage cell line J774.A1. Based on the results, three hybrids showed the highest antileishmanial activity. However, they revealed low cytotoxicity. Hybrid 6j was the most potent compound against both the forms of all leishmanial types, with IC50 = 13.5 and 11.9 µg/mL for L. major, 37.5 and 25 µg/mL for L. tropica, 17.5 and 20 µg/mL for L. infantum (MCAN/IR//96/LON49) and 35.5 and 30 µg/mL for L. infantum (MCAN/ES/98/LIM-877), respectively. Finally, molecular docking and molecular dynamics simulations were also performed to identify possible mechanism antileishmanial activity.Communicated by Ramaswamy H. Sarma.

The effect of mutation on neurotoxicity reduction of new chimeric reteplase, a computational study.

Background and purpose: Excitotoxicity in nerve cells is a type of neurotoxicity in which excessive stimulation of receptors (such as N-methyl-d-aspartate glutamate receptors (NMDAR)) leads to the influx of high-level calcium ions into cells and finally cell damage or death. This complication can occur after taking some of the plasminogen activators like tissue plasminogen activator and reteplase. The interaction of the kringle2 domain in such plasminogen activator with the amino-terminal domain (ATD) of the NR1 subunit of NMDAR finally leads to excitotoxicity. In this study, we assessed the interaction of two new chimeric reteplase, mutated in the kringle2 domain, with ATD and compared the interaction of wild-type reteplase with ATD, computationally. Experimental approach: Homology modeling, protein docking, molecular dynamic simulation, and molecular dynamics trajectory analysis were used for the assessment of this interaction. Findings/Results: The results of the free energy analysis between reteplase and ATD (wild reteplase: -2127.516 ± 0.0, M1-chr: -1761.510 ± 0.0, M2-chr: -521.908 ± 0.0) showed lower interaction of this chimeric reteplase with ATD compared to the wild type. Conclusion and implications: The decreased interaction between two chimeric reteplase and ATD of NR1 subunit in NMDAR which leads to lower neurotoxicity related to these drugs, can be the start of a way to conduct more tests and if the results confirm this feature, they can be considered potential drugs in acute ischemic stroke treatment.

Computational design of newly engineered DARPins as HER2 receptor inhibitors for breast cancer treatment.

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

Homology modeling of human CCR5 and analysis of its binding properties through molecular docking and molecular dynamics simulation.

In this study, homology modeling, molecular docking and molecular dynamics simulation were performed to explore structural features and binding mechanism of some inhibitors of chemokine receptor type 5 (CCR5), and to construct a model for designing new CCR5 inhibitors for preventing HIV attachment to the host cell. A homology modeling procedure was employed to construct a 3D model of CCR5. For this procedure, the X-ray crystal structure of bovine rhodopsin (1F88A) at 2.80Å resolution was used as template. After inserting the constructed model into a hydrated lipid bilayer, a 20ns molecular dynamics (MD) simulation was performed on the whole system. After reaching the equilibrium, twenty-four CCR5 inhibitors were docked in the active site of the obtained model. The binding models of the investigated antagonists indicate the mechanism of binding of the studied compounds to the CCR5 obviously. Moreover, 3D pictures of inhibitor-protein complex provided precious data regarding the binding orientation of each antagonist into the active site of this protein. One additional 20 ns MD simulation was performed on the initial structure of the CCR5-ligand 21 complex, resulted from the previous docking calculations, embedded in a hydrated POPE bilayer to explore the effects of the presence of lipid bilayer in the vicinity of CCR5-ligand complex. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes.

Finding a prospective dual-target drug for the treatment of coronavirus disease by theoretical study.

Spike protein of coronavirus is a key protein in binding and entrance of virus to the human cell via binding to the receptor-binding domain (RBD) domain of S1 subunit to peptidase domain region of ACE2 receptor. In this study, the possible effect of 24 antiviral drugs on the RBD domain of spike protein was investigated via docking and molecular dynamics simulation for finding a dual-target drug. At first, all drugs were docked to the RBD domain of spike protein, and then all complexes and free RBD domains were separately used for molecular dynamics simulation for 50 ns via amber18 software. The simulation results showed that 10 ligands from 28 ligands were separated from the RBD domain, and among 18 remained ligands, baloxavir marboxil, and danoprevir drugs, besides endonuclease activity and protease inhibitory, can bind to key residues of the RBD domain. Then these drugs have a dual target and should be more effective than current drugs, and experimental studies should be done on baloxavir marboxil and danoprevir as more potential drugs for coronavirus disease Communicated by Ramaswamy H. Sarma.

In-silico design of peptides for inhibition of HLA-A*03-KLIETYFSK complex as a new drug design for treatment of multiples sclerosis disease.

Multiple sclerosis is recognized as a chronic inflammatory disease. Human leukocyte antigen (HLA) plays an important role in initiating adaptive immune responses. HLA class I is present in almost all nucleated cells and presents the cleaved endogenous peptide antigens to cytotoxic T cells. HLA-A*03 is one of the HLA class I alleles, which is reported as substantially related HLA to MS disease. In 2011, the structure of the HLA-A*03 in complex was identified with an immunodominant proteolipid protein (PLP) epitope (KLIETYFSK). This complex has been reported as an important autoantigen-presenting complex in MS pathogenesis. In this study, new peptides were designed to bind to this complex that may prevent specific pathogenic cytotoxic T cell binding to this autoantigen-presenting complex and CNS demyelination. Herein, 14 new helical peptides containing 19 amino acids were designed and their structures were predicted using the PEP-FOLD server. The binding of each designed peptide to the mentioned complex was then performed. A mutation approach was used by the BeAtMuSiC server to improve the binding affinity of the designed peptide. In each position, amino acid substitutions leading to an increase in the binding affinity of the peptide to the mentioned complex were determined. Finally, the resulting complexes were simulated for 40 ns using AMBER18 software. The results revealed that out of 14 designed peptides, "WRYWWKDWAKQFRQFYRWF" peptide exhibited the highest affinity for binding to the mentioned complex. This peptide can be considered as a potential drug to control multiple sclerosis disease in patients carrying the HLA-A*03 allele.

Absorption of daunorubicin and etoposide drugs by hydroxylated and carboxylated carbon nanotube for drug delivery: theoretical and experimental studies.

Anti-cancer daunorubicin and etoposide drugs are mostly used in chemotherapy medicine to treat a wide variety of cancers. Many of the side effects and specific delivery to a target tissue are the main challenges of using chemotherapeutic agents. To avoid serious toxic side effects and improve treatment outcomes, functionalized carbon nanotubes (f-CNTs) are considered promising nano-carriers for the delivery of chemotherapeutic drugs to cancerous cells. We examined the effects of -OH and -COO- groups on CNTs surface for absorption of two anticancer drugs including daunorubicin and etoposide using molecular dynamics simulation and experimental assays. To evaluate the absorption of each drug in each CNT, the complexes of drugs/CNTs in water were simulated separately. Theoretical investigation demonstrated that CNT-OH and CNT-COO- are more suitable for absorption of daunorubicin and etoposide, respectively. Experimental findings also confirmed molecular dynamics simulation results. Communicated by Ramaswamy H. Sarma.

In silico screening and molecular dynamics simulations toward new human papillomavirus 16 type inhibitors.

Background and purpose: Human papillomavirus (HPV) is known as the main reason for cervical cancer. According to carcinogenic risk, HPV can be located into two classes, counting the low-risk virus, which is the main cause of genital warts and low-grade cervical epithelial lesions. HPV-16 is one of the high-risk HPV subtypes in the spectrum of cervical diseases. Experimental approach: The PubChem database was screened in order to identify potential anti-HPV hits followed by ADMET predictions. Then, molecular docking was performed to improve the accuracy of screening and also to find the details of the interactions of the hit compounds with the active site. Finally, molecular dynamic (MD) simulations and free binding energy on top-ranked structures CID_73212812, CID_91059286, CID_69838075, cidofovir, and jaceosidin were carried out with protein to compute the interaction energies and stability of the top-ranked compounds at the active site. Findings/Results: Based on molecular docking studies, three compounds including CID_73212812, CID_91059286, and CID_69838075 exhibited the best results among compounds against the E6 protein of HPV-16. Furthermore, RMSD, RMSF, hydrogen binds, Rg, and energy analysis during MD simulation certainly indicated the stable binding of selected compounds with E6 protein of HPV-16 active site. Conclusion and implications: Docking and MD results revealed that hydrophobic contacts and optimum hydrogen bonds were determinant factors in the interactions of hits and the E6 protein of HPV-16. In addition, the binding energy portions exposed that Van der Waals and non-polar interactions were fundamental factors in the molecule binding.