Molecular Modeling Software Research Articles

Potential effects of specific natural bioactive compounds in medicinal plants, essential oils and probiotics related to SARS-CoV-2 (COVID-19)

According to the World Health Organization, the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or COVID 19 has caused a pandemic around the world. The rapid infection has posed significant threats to international health and the economy. Till now, there is no treatment available. This contribution focuses on specific phytochemicals, essential oils and probiotics against SARS-CoV-2. Different electronic scientific databases and search engines were employed. The potential effects of phenolics, flavonoids, tannins, alkaloids, saponins and essential oils from different edible sources as well as probiotics against SARS-CoV-2 and coronaviruses have been reviewed. Inhibition mechanisms on SARS-CoV-2 and other coronaviruses either experimented or predicted by molecular docking modeling software were presented. The confirmed compounds belong to the alkaloids, tannins and terpenoides bioactive classes as pedunculagin, tercatain, punicalin, punicalagin, punicalin, geraniin, chebulagic acid, punicalagin, emetine and ginkgolide A can be preventing the infection or introducing treatments against SARS-CoV-2 and other coronaviruses. Lactobacillus plantarum strain N4, Enterococcus faecium NCIMB 10415, Lactobacillus salivarius prevented the infection by trapping the coronavirus or stimulated the cellular defense by the production of nitric oxide. Utilize the rich plants with bioactive compounds or use them in the preparation of functional foods is a simple way to provide people with protection against SARS-COV-2.

Synthesis, In silico and Biological Studies of Thiazolyl-2h-chromen-2-one Derivatives as Potent Antitubercular Agents.

A series of new six thiazolyl-2-amine-based Schiff base derivatives (4a-4f) were synthesized by a sequential multistep reaction starting with Salicylaldehyde. All the Schiff base derivatives were screened in-vitro for their antibacterial activity against Mycobacterium tuberculosis (H37RV strain) ATCC No-27294. The synthesized compounds were characterized by FTIR, 1H-NMR, 13C-NMR and Mass spectrometry. Among the compounds tested, 4c and 4f derivatives exhibited potent antitubercular activity against M. tuberculosis at MIC 6.25 μg/mL. We extended our study to explore the inhibition mechanism by conducting molecular docking analysis by using Schrodinger's molecular modeling software. All the newly synthesized compounds were found to be in-silico AMES test non-toxic and non-carcinogens. The good Qikprop's Absorption, Distribution, Metabolism and Excretion (ADMET) would definitely help the researchers in order to make more potent Anti-TB agents.

Biomimetic Affinity Ligands for Protein Purification.

The development of sophisticated molecular modeling software and new bioinformatic tools, as well as the emergence of data banks containing detailed information about a huge number of proteins, enabled the de novo intelligent design of synthetic affinity ligands. Such synthetic compounds can be tailored to mimic natural biological recognition motifs or to interact with key surface-exposed residues on target proteins, and are designated as "biomimetic ligands". A well-established methodology for generating biomimetic or synthetic affinity ligands integrates rational design with combinatorial solid-phase synthesis and screening, using the triazine scaffold and analogs of amino acid side chains to create molecular diversity.Triazine-based synthetic ligands are nontoxic, low-cost, and highly stable compounds that can replace advantageously natural biological ligands in the purification of proteins by affinity-based methodologies.

Design, Synthesis, In vitro and In silico Evaluation of New Hydrazonebased Antitumor Agents as Potent Akt Inhibitors

Background: Akt is overexpressed or activated in a variety of human cancers, including gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted to the discovery of potent antitumor drugs targeting Akt. Objectives: The objective of this work was to identify potent anticancer agents targeting Akt. Methods: New hydrazone derivatives were synthesized and investigated for their cytotoxic effects on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results and Discussion: Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells (with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin- 2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the compound also complies with Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis inducer targeting Akt.

Experimental and Molecular Level Analysis of the Tribological and Oxidative Properties of Chaulmoogra Oil

This study introduces chaulmoogra oil as a base stock for lubricant formulation. The tribological properties of chaulmoogra oil are evaluated by quantitative structure-property relation (QSPR) technique using the molecular modelling package Spartan 18. The quantum chemical calculations were performed on a typical molecule of chaulmoogra oil and its constituent fatty acids. The orbital energy gap of the constituent fatty acids in chaulmoogra oil is 7.37 eV and that of chaulmoogra oil molecule is 6.8 eV, which is less than that of the lauric acid, the main constituent of coconut oil (7.78 eV). Orbital energy gap predicts a better tribological performance for chaulmoogra oil, and the four ball test result is in agreement with this prediction. Oxidative property of chaulmoogra oil is tested by isothermal thermogravimetric/differential thermal analysis (TGA/DTA) and compared with different oils. Weight gain in oxygen is only 0.02% for chaulmoogra oil and showed better oxidative stability among all other tested oils.

Structure based drug discovery and in vitro activity testing for DNA gyrase inhibitors of Salmonella enterica serovar Typhi

The emerged resistance in Typhoidal Salmonella has limited the treatment options for typhoid fever. In this scenario, there is a need to find alternate treatment modalities against this pathogen. Amongst the therapeutic agents currently being used to treat enteric fever, quinolones have enjoyed considerable success since past three decades. These drugs act upon DNA gyrase and the acquired resistance is due to mutations at Ser83 and Asp87 of gyrase A subunit. In the present study DNA gyrase enzyme was targeted to seek out potential new inhibitors which are not affected by these mutations. Molecular modelling and docking studies were performed in Schrödinger’s molecular modelling software. Homology model of DNA gyrase-DNA complex was built using templates 1AB4 and 3LTN. Molecular dynamic simulations were performed in SPC solvent for 100 ns. Total 17,900,742 drug like molecules were downloaded from ZINC library of chemical compounds. The Glide XP score of the compounds ranged from −5.285 to −13.692. All the ligands bound at the four base pair staggered nick in the DNA binding groove of DNA gyrase enzyme with their aromatic rings intercalating between the bases of two successive nucleotides stabilized by π - π stacking interactions. The binding pocket of DNA gyrase B comprising conserved residues Lys 447, Gly 448, Lys 449, Ile 450, Leu 451, Gln 465 and Val 467 interacts with the ligand molecules through van der Waals interactions. The MIC (minimum inhibitory concentration), MBC (minimum bactericidal concentration) and IC50 of the tested compounds ranged from 500 to 125 mg/L, 750 to 500 mg/L and 100 to 12.5 mg/L, respectively. The selected hits bind to quinolone binding pocket, but their mode of binding and conformation is different to fluoroquinolones, and hence, their binding is not affected by mutations at Ser83 or Asp87 positions. These lead compounds can be further explored as a scaffold to design inhibitors against DNA gyrase to bypass quinolone resistance.

A New Series of Antileukemic Agents: Design, Synthesis, In Vitro and In Silico Evaluation of Thiazole-Based ABL1 Kinase Inhibitors.

After the approval of imatinib, more than 25 antitumor agents targeting kinases have been approved, and several promising candidates are at various stages of clinical evaluation. Due to the importance of the thiazole scaffold in targeted anticancer drug discovery, the goal of this work is to identify new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of Chronic Myeloid Leukemia (CML). New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on the K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on Mitogen-Activated Peripheral Blood Mononuclear Cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on K562 cell line and inhibitory effects on eight different Tyrosine Kinases (TKs), including ABL1 kinase. In order to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), a molecular docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger's Molecular modelling package was used to predict the pharmacokinetic properties of compounds 2a-p. 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 μM similar to imatinib (IC50= 6.84±1.11μM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells. Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound 2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17μM). According to molecular docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase, forming significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's rule of five and Jorgensen's rule of three. Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment of CML.

Synthesis and In Silico Molecular Docking Studies on Substituted Piperic Acid Derivatives as Inhibitors of Bacterial DNA Gyrase

Piperine or piperic acid was isolated from fruits of Piper nigrum and had been reported as pharmacological valuable bioactive constituents. Keeping in view, a series of piperic acid-based N heterocyclic's derivatives were synthesized and evaluated for antibacterial activity. All these prepared ligands were docked to study the molecular interactions and binding affinities against the protein PDB ID: 5 CDP. To meet the real need of newer antibacterials, we designed and synthesized scaffolds with good antibacterial activity. The obtained antibacterials have been validated in terms of ligand-protein interaction and thus prove to build up as good drug candidates. Antibacterial activity of the compounds were carried out against bacterial strains; three Grampositive and three Gram-negative bacterial strains using agar well diffusion method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrödinger molecular modeling package by Maestro 11.0. Compounds BC 28, BC 32, and BC 33 exhibits antibacterial activity along with Glide docking score of -8.580, -9.753 kcal/mol, and -8.813 kcal/mol, respectively. Docking studies explained hydrogen bonding, pi-pi, and hydrophobic interactions with amino acid residues which explain the binding affinity of the most docked ligand with protein. In the present study, substituted piperic acid was synthesized and evaluated as antibacterial compared with standard drug ciprofloxacin and results interpret that having nitrogen as heteroatom in the heterocyclic nucleus found to be more potent than the standard drug ciprofloxacin. On comparing, substitution with electron-donating groups generates excellent antibacterial potential against the bacterial strains. It was also proved that having substitution with electron-donating groups on meta and para position with triazoline ring system exhibits greater potential while compounds which have a meta- electron-donating substituent showed lesser activity with thiazole nucleus. In addition, structure-based activities of the prepared analogs were discussed under Structure-Activity Relationship (SAR) section.

Synthesis, In vitro and In silico Evaluation of a Series of Pyrazolines as New Anticholinesterase Agents

Background: Pyrazolines, electron-rich nitrogen carriers, are of great importance due to their potential applications for the treatment of many diseases including inflammation, infectious diseases and neurodegenerative disorders. Objectives: The purpose of this work was to synthesize new pyrazoline derivatives and evaluate their anticholinesterase effects. Methods: 1-Aryl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (1-7) were synthesized via the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(piperidin-1-yl)phenyl]prop-2- en-1-one with arylhydrazine hydrochloride derivatives in acetic acid, whereas 1-aryl-5-[4- (morpholin-4-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (8-14) were obtained by the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one with arylhydrazine hydrochloride derivatives in acetic acid. Their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were determined using a modification of Ellman’s spectrophotometric method. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were performed using Schrödinger’s Maestro molecular modeling package. Results: In general, piperidine derivatives were found to be more effective than morpholine derivatives on cholinesterases (ChEs). 1-Phenyl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)- 4,5-dihydro-1H-pyrazole (1) and 1-(4-cyanophenyl)-5-[4-(piperidin-1-yl)phenyl]-3-(3,4- dimethoxyphenyl)-4,5-dihydro-1H-pyrazole (7) were identified as the most effective AChE inhibitors in this series with 40.92% and 38.98%, respectively. Compounds 1 and 7 were docked into the active site of human AChE (PDB code: 4EY7). Both the compounds were found to be capable of forming π-π stacking interactions with Trp286. Based on in silico ADME studies, these compounds are expected to have reasonable oral bioavailability. Conclusion: In the view of this work, the structural modification of the identified agents is going on for the generation of new anticholinesterase agents with enhanced efficacy.

A Series of Furan-based Hydrazones: Design, Synthesis, and Evaluation of Antimicrobial Activity, Cytotoxicity and Genotoxicity

Background: Hydrazones, frequently occurring motifs in many bioactive molecules, have attracted a great deal of interest as potent antimicrobial agents. Objective: The aim of this work was to design and synthesize new hydrazone-based antimicrobial agents. Methods: 4-[2-((5-Arylfuran-2-yl)methylene)hydrazinyl]benzonitrile derivatives (1-10) were obtained via the reaction of 4-cyanophenylhydrazine hydrochloride with 5-arylfurfurals. Compounds 1-10 were evaluated for their antimicrobial effects using a broth microdilution method. Their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cell line were determined using XTT assay. The most effective antimicrobial agents were investigated for their genotoxic effects using Ames MPF assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results: The antifungal effects of the compounds were more significant than their antibacterial effects. Compound 5 bearing 3-nitrophenyl moiety was the most potent antifungal agent against Candida albicans, Trichoderma harzianum and Fusarium species, whereas compound 10 bearing 4- chloro-2-nitrophenyl moiety was the most effective antifungal agent on Aspergillus ochraceus. According to XTT and Ames MPF assays, these compounds were neither cytotoxic nor genotoxic at the concentrations tested. Docking studies suggested that these compounds showed good affinity to the active site of lanosterol 14α-demethylase (CYP51) (PDB code: 5V5Z) and interacted with the key residues such as Hem601 and Cys470. Based on in silico ADME studies, the compounds are expected to have high oral bioavailability. Conclusion: According to the in vitro and in silico studies, compounds 5 and 10 stand out as potential orally bioavailable antifungal agents for further studies.

A Digital Workflow Supporting the Selection of Solvents for Optimizing the Crystallizability of p-Aminobenzoic Acid

We present a grid-based molecular modeling approach and software application for screening the solute–solvent and solute–solute interactions of organic molecules. This tool can provide a deeper und...

Mechanosensitive Piezo1 ion channel protein (PIEZO1 gene): update and extended mutation analysis of hereditary xerocytosis in India.

Hereditary xerocytosis (HX), also known as dehydrated stomatocytosis (DHSt) is a dominantly inherited genetic disorder exhibiting red cell membrane dehydration caused by the loss of the monovalent cation K+ and water. Variants in mechanosensitive Piezo ionic channels of the PIEZO1 gene are the primary cause of HX. We have utilized high throughput and highly precise next-generation sequencing (NGS) to make a diagnosis and examine the genotype-phenotype relationship in inflexible HX cases. Seven unrelated patients with unexplained hemolytic anemia were scrutinized with a panel probing 8000 genes related to congenital anemia. Targeted next-generation sequencing identified 8 missense variants in the PIEZO1 gene in 7 unrelated Indian patients. Three of the 8 variants are novel (c.1795G > C, c.2915G > A, c.7372T > C) and the remaining five (c.4082A > G, c.6829C > A, c.7374C > G, c.7381G > A, c.7483_7488dup) are previously reported. The variants have been validated by Sanger sequencing. One patient with autosomal dominant mutation (c.7372T > C) is associated with iron refractory iron deficiency anemia. Of the 7 patients, one has HX in combination with a novel homozygous variant (c.994G > A) in the PKLR gene causing PK deficiency resulting in severe clinical manifestations with phenotypic variability. In silico prediction using bioinformatics tools were used to study the possible damaging effects of the novel variants. Structural-functional analysis of the novel variants was investigated by molecular modeling software (PyMOL and Swiss PDB). These results encompass the heterogeneous behavior of mechano-sensitive Piezo1 protein observed in HX patients in India. Moreover, NGS imparted a subtle, economical, and quick tool for understanding the genetic cause of undiagnosed cases of congenital hemolytic anemia. NGS grants a potential technology integrating clinical history together with molecular report profiting in such patients and their families.

Atomistic and coarse-grained simulations of membrane proteins: A practical guide.

Membrane proteins are amphipathic macromolecules whose exposed hydrophobic surfaces promote interactions with lipid membranes. Membrane proteins are remarkably diverse in terms of chemical composition and correspondingly, their biological functions and general biophysical behavior. Conventional experimental techniques provide an approach to study specific properties of membrane proteins e.g. their surface features, the nature and abundance of stabilizing intramolecular forces, preferred bilayer orientation, and the characteristics of their annular lipid shells. Molecular modeling software-and in particular, the suite of molecular dynamics algorithms-enables a more comprehensive exploration of dynamic membrane protein behavior. Molecular dynamics methods enable users to produce stepwise trajectories of proteins on arbitrary spatiotemporal scales that enable the easy identification of dynamic interactions that are beyond the scope of conventional analytical techniques. This article explains the molecular dynamics theoretical framework and popular step-by-step approaches for simulating membrane proteins in planar, and to a lesser extent, nonplanar lipid geometries. We detail popular procedures and computational tools that produce well-packed configurations of lipids and proteins and additionally, the efficient molecular dynamics simulation algorithms that reproduce their dynamic interactions.

Computational and Experimental Study on the Stability of Nanofluids

Nanofluids, which are suspensions of nanoparticles dispersed in a base fluid, have remarkable potential in a wide range of applications. However, the stability of the nanofluid has remained a challenge and a matter of concern. A lot of research, development work and reviews have been conducted on the preparation and stability of nanofluids. In this study, calculation of solubility parameter values using a molecular modelling software were performed to aid the screening of nanoparticles that are compatible with the base fluid. The solubility parameter is the numerical representation of the solvency behavior between two molecules. A molecular modelling software was used to study the solubility parameter values of nanoparticles to determine their compatibility with the base fluids. To validate the model, the computed values were compared against published literature and it was shown that the model has achieved more than 95% accuracy. The simulations were verified with experimental work with varying concentration of nanoparticles in brine solution and deionized water. Experimental results showed that zinc oxide nanoparticles demonstrated the best compatibility with the base fluid, which tally with the simulation.

Computational Methods for Biochemical Simulations Implemented in GAMESS.

Computational methods for modeling biochemical processes implemented in GAMESS package are reviewed; in particular, quantum mechanics combined with molecular mechanics (QM/MM), semi-empirical, and fragmentation approaches. A detailed summary of capabilities is provided for the QM/MM implementation in QuanPol program and the fragment molecular orbital (FMO) method. Molecular modeling and visualization packages useful for biochemical simulations with GAMESS are described. GAMESS capabilities with corresponding references are tabulated for reader'sconvenience.

Virtual Screening of Inhibitors for Chitosanases EAG1

Chitosanases EAG1 is a classical glycoside hydrolase from Bacillus ehimensis. The previous researches showed that this Chitosanases can not only hydrolyze the b1,4-glycosidic bonds of chitosan to COS in different sizes but also keep a high catalytic activity in organic, which was useful for producing chitooligosaccharides and GlcN for use in the food and pharmacological industries. While it is instable in the liquid state. This shortcoming seriously restricts its industrial application. Here we used the modeled structure of EAG1 and the molecular modeling software package to screen the free chemical database ZINC. Moreover, the strategies including “initial filter” and consensus scoring were applied to accelerate the process and improve the success rate of virtual screening. Finally, five compounds were screened and they were purchased or synthetized to test their binding affinity against EAG1. The test results showed that one of them could inhibit the enzyme with an apparent Ki of 1.5 μM. The result may take the foundation for further inhibitor screening and design against EAG1 and the screened compound may also help to improve the liquid stability of EAG1 and expand its industrial application.

Synthesis, biological evaluation and molecular docking of pyrimidine and quinazoline derivatives of 1,5-benzodiazepine as potential anticancer agents

A new series of Pyrimidine (A, D and F) and quinazoline (B, C and E) analogues of 1,5-benzodiazepines were prepared via its nitrile-derived amidoximes in and nitrilium ions, respectively using one pot Domino reaction with DMAD in presence of DABCO catalyst and benzanilide in presence of Tf2O and 2-chloropyridine. The prepared molecules were examined for their biological property namely apoptotic and antiproliferative effects through cell cycle arrest using breast cancer cell line of human (MCF-7). Receptor-ligand interactions were studied on human epidermal evolution factor receptor (HER-2) with the help of molecular docking using Autodock 4.2.6 molecular modeling software. All the compounds demonstrated inhibitory effects on cell proliferation in a concentration dependent fashion (20–100 μg/mL). Notably, compound C exhibited highest inhibitory activity and caused inhibition of S and G2 phase in cell cycle arrest via caspase dependent apoptotic pathway in MCF-7 cells lines.

Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency

BackgroundAlpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the ‘Z’ and ‘S’ variants – single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V. However, SERPINA1 is highly polymorphic, with numerous potentially clinically relevant variants reported. Novel variants continue to be discovered, and without reports of pathogenicity, it can be difficult for clinicians to determine the best course of treatment.MethodsWe assessed the utility of next-generation sequencing (NGS) and predictive computational analysis to guide the diagnosis of patients suspected of having AATD. Blood samples on serum separator cards were submitted to the DNA1 Advanced Screening Program (Biocerna LLC, Fulton, Maryland, USA) by physicians whose patients were suspected of having AATD. Laboratory analyses included quantification of serum AAT levels, qualitative analysis by isoelectric focusing, and targeted genotyping and NGS of the SERPINA1 gene. Molecular modeling software UCSF Chimera (University College of San Francisco, CA) was used to visualize the positions of amino acid changes as a result of rare/novel SNVs. Predictive software was used to assess the potential pathogenicity of these variants; methods included a support vector machine (SVM) program, PolyPhen-2 (Harvard University, Cambridge, MA), and FoldX (Centre for Genomic Regulation, Barcelona, Spain).ResultsSamples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were probably deleterious, and two were possibly deleterious. For the majority of probably/possibly deleterious SNVs (I50N, P289S, M385T, M221T, D341V, V210E, P369H, V333M and A142D), the mechanism is probably via disruption of the packed hydrophobic core of AAT. Several deleterious variants occurred in combination with more common deficiency alleles, resulting in very low AAT levels.ConclusionsNGS and computational modeling are useful tools that can facilitate earlier, more precise diagnosis, and consideration for AAT therapy in AATD.

It’s an Interesting MOF, but Is It Stable?

The mechanical stability of metal-organic framework (MOF) structures is key to their functionality. In this issue of Matter, Moghadam et al. use high-throughput simulations and machine learning to derive structure-mechanical properties and predict bulk moduli of MOFs from a few physical parameters.

Comprehensive Study on Thiadiazole-Based Anticancer Agents Inducing Cell Cycle Arrest and Apoptosis/Necrosis Through Suppression of Akt Activity in Lung Adenocarcinoma and Glioma Cells.

Akt is considered as an attractive target for anticancer drug discovery and development and therefore extensive efforts have been devoted to the discovery of new potent anticancer agents targeting Akt. Due to the importance of thiadiazoles for anticancer drug discovery, herein eight 1,3,4-thiadiazole derivatives were investigated for their cytotoxic effects on C6 rat glioma and A549 human lung adenocarcinoma cell lines using the MTT assay. The effects of the most promising anticancer agents on apoptosis, caspase-3 activation, mitochondrial membrane potential, and cell cycle arrest were determined on a BD FACSAria (I) flow cytometer. Akt activity was measured in the C6 and A549 cell lines using an ELISA colorimetric method. Schrödinger's Maestro molecular modeling package was used to explore the possible binding modes of compounds 3 and 8 in the active site of Akt enzyme (PDB code: 3OW4). N-(4-Chlorophenyl)-2-[(5-((4-nitrophenyl)amino)-1,3,4-thiadiazol-2-yl)thio]acetamide (3) and N-(6-nitrobenzothiazol-2-yl)-2-[(5-((4- nitrophenyl)amino)-1,3,4-thiadiazol-2-yl)thio]acetamide (8) induced apoptosis and cell cycle arrest in the C6 cell line through inhibition of Akt activity (92.36% and 86.52%, respectively). The docking results of compounds 3 and 8 indicated that π-π interactions, H bonds, and salt-bridge formation were responsible for the observed Akt inhibitory activity. According to in vitro and docking studies, compounds 3 and 8 stand out as promising antiglioma agents.