Molecular Modeling Approach Research Articles

Experimental and molecular modelling approach for rapid adsorption of Bisphenol A using Zr and Fe based metal–organic frameworks

The synthesized highly porous functionalized metal–organic frameworks (MOFs) are the solution for the rapid removal of toxic pollutants from wastewater. Bisphenol A (BPA) which consists of a derivative of phenol was identified as the primary pollutant in environmental waters and requires elimination for a sustainable and greener environment. In this work, we reported highly porous and stable Zr and Fe–based metal–organic frameworks as adsorbents for the removal of BPA in an aqueous solution. In this study, MIL–88(Fe) (MIL stands for Matériaux de l’Institut Lavoisier) and UiO–66(Zr) (UiO stands for University of Oslo) were synthesized by solvothermal techniques and characterized by fourier transformed infrared spectroscopy (FTIR), x–ray diffraction (XRD), energy–dispersive x–ray spectroscopy (EDX), field emission scanning electron microscopy (FESEM), scanning electron microscopy (SEM) and nitrogen adsorption–desorption measurements. MIL–88(Fe) and UiO–66(Zr)had 1242 and 1421 mg2/g surface area, respectively. In the experimental study, the UiO–66(Zr) and MIL–88(Fe)removed 99.25 and 98.36 % BPA, respectively. Compared to MIL–88(Fe), UiO–66(Zr) showed faster adsorption of BPA. The process was exothermic and spontaneous. The pseudo–second order model suited the kinetics studies well, while the Langmuir model fit the MIL–88(Fe) and UiO–66(Zr)isotherms. Molecular docking was used to study the surface interactions of MIL–88(Fe) and UiO–66(Zr) with BPA.The process involved van der Waals and hydrogen interactions between BPA with MIL–88(Fe) and UiO–66(Zr) surfaces. Both MOFs proved to have high efficacy and appropriateness for the practical application of BPA adsorption from an aqueous solution.

Exploring the intercalation binding of tiamulin with DNA using multispectroscopy and a molecular modelling approach.

The binding of tiamulin with calf thymus DNA was systematically investigated using multispectroscopy and molecular modelling techniques. For DNA, once tiamulin was added, viscosity (η) and melting temperature (Tm ) both exhibited an uptrend. The fluorescence performance of the tiamulin-DNA complex did not change with the ionic strength changes. The binding constant (Ka ) of tiamulin for single-stranded DNA (ssDNA, 1.48 × 104 M-1 ) was obviously higher than that for double-stranded DNA (dsDNA, 9.51 × 103 M-1 ) at 291 K. The helix structure became looser and the base stack force became stronger for DNA due to the presence of tiamulin as seen from circular dichroic (CD) spectra. The intercalation binding mode of tiamulin with DNA was disclosed. Molecular modelling also revealed tiamulin inserting into the base pairs with the lowest binding free energy of -18.73 kJ mol-1 using van der Waals forces as well as hydrogen bonds.

Preventive behavior of phenol Schiff bases on mild steel corrosion in acidic medium part A: Experimental and molecular modeling approach

Corrosion is among the challenges most industries face. Corrosion inhibitors are developed to fix the issues of corrosion in these industries. For this reason, the corrosion inhibitive properties on mild steel (MS) of two phenolic Schiff bases named (E)-4-(1-((3-hydroxyphenyl)imino)ethyl)benzene-1,3-diol (PSB1) and (E)-4-(1-(pyridin-2 ylimino)ethyl)benzene-1,3-diol (PSB2) were examined. Gravemitry and electrochemical techniques are utilized such as experimental methods. Beside, SEM and EDS studied the surface to validate the deposition of the inhibitors. The protective efficacy for inhibitors improves with decreasing temperature and rises with substrate amounts, nearing 90.3% (PSB1) and 90.9% (PSB2) at 303 K and 1 × 10–3 M, respectively. Thus, PSB1 and PSB2 operated as the inhibitor of the mixed form. Both ligands adhere pursuant to the Langmuir adsorption isotherm model. Furthermore, the adsorption on the surface has been proven by the SEM and EDS experiments. The results of the computer modeling are fully confirmed by the experimental findings.

Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N—H···O and C—H···O hydrogen bonds and C—H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C—H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

An integrated approach reveals how lipo-chitooligosaccharides interact with the lysin motif receptor-like kinase MtLYR3.

N‐acetylglucosamine containing compounds acting as pathogenic or symbiotic signals are perceived by plant‐specific Lysin Motif Receptor‐Like Kinases (LysM‐RLKs). The molecular mechanisms of this perception are not fully understood, notably those of lipo‐chitooligosaccharides (LCOs) produced during root endosymbioses with nitrogen‐fixing bacteria or arbuscular mycorrhizal fungi. In Medicago truncatula, we previously identified the LysM‐RLK LYR3 (MtLYR3) as a specific LCO‐binding protein. We also showed that the absence of LCO binding to LYR3 of the non‐mycorrhizal Lupinus angustifolius, (LanLYR3), was related to LysM3, which differs from that of MtLYR3 by several amino acids and, particularly, by a critical tyrosine residue absent in LanLYR3. Here, we aimed to define the LCO binding site of MtLYR3 by using molecular modelling and simulation approaches, combined with site‐directed mutagenesis and LCO binding experiments. 3D models of MtLYR3 and LanLYR3 ectodomains were built, and homology modelling and molecular dynamics (MD) simulations were performed. Molecular docking and MD simulation on the LysM3 identified potential key residues for LCO binding. We highlighted by steered MD simulations that in addition to the critical tyrosine, two other residues were important for LCO binding in MtLYR3. Substitution of these residues in LanLYR3‐LysM3 by those of MtLYR3‐LysM3 allowed the recovery of high‐affinity LCO binding in experimental radioligand‐binding assays. An analysis of selective constraints revealed that the critical tyrosine has experienced positive selection pressure and is absent in some LYR3 proteins. These findings now pave the way to uncover the functional significance of this specific evolutionary pattern.

Exploring PI3Kγ binding preference with Eganelisib, Duvelisib, and Idelalisib via energetic, pharmacophore and dissociation pathway analyses

Phosphatidylinositol 3-kinase (PI3K) is the central regulator of cellular functions and is suggested as a target for various diseases; thus, effective PI3K inhibitors provide a promising opportunity for the pharmaceutical intervention of many diseases. Among them, PI3Kγ has received more attention because of its essential role in immune signaling. However, the development of novel selective PI3Kγ inhibitors is a major challenge due to the high sequence homology across the class I PI3K isoforms. Therefore, understanding the substrate specificity and receptor-ligand interaction of PI3Kγ would be an appropriate strategy for the rational design of potent γ-selective inhibitors. In this study, by combining various molecular modeling approaches (including classic and enhanced sampling molecular dynamics (MD) simulations, end-point binding free energy calculations, and pharmacophore models), three quinolinone core-containing inhibitors, Idelalisib/CAL-101, Duvelisib/IPI-145, and Eganelisib/IPI-549, were employed to reveal the selective binding mechanisms targeting PI3Kγ. The classic MD and free energy calculations highlight the significant interaction and some key residues for the selective binding against PI3Kγ. Furthermore, the dissociation pathway analysis based on umbrella sampling simulations reveals that hydrophobic interactions are dominant for binding of the three ligands during the dissociation processes, and cooperation between the P-loop and the ligands always exists in the binding/dissociation process. Finally, the pharmacophore model revealed that IPI-549 contains a unique hydrophobic feature, and PI3Kγ exhibits an important hydrogen bond donor feature of hydrogen amide. These findings may provide some important information for the rational design and optimization of PI3Kγ-selective inhibitors.

Neurotoxicological Profiling of Paraquat in Zebrafish Model.

Paraquat is a polar herbicide protecting plant products against invasive species, it requires careful manipulation and restricted usage because of its harmful potentials. Exposure to paraquat triggers oxidative damage in dopaminergic neurons and subsequently causes a behavioral defect in vivo. Thereby, persistent exposure to paraquat is known to increase Parkinson's disease risk by dysregulating dopaminergic systems in humans. Therefore, most studies have focused on the dopaminergic systems to elucidate the neurotoxicological mechanism of paraquat poisoning, and more comprehensive neurochemistry including histaminergic, serotonergic, cholinergic, and GABAergic systems has remained unclear. Therefore, in this study, we investigated the toxicological potential of paraquat poisoning using a variety of approaches such as toxicokinetic profiles, behavioral effects, neural activity, and broad-spectrum neurochemistry in zebrafish larvae after short-term exposure to paraquat and we performed the molecular modeling approach. Our results showed that paraquat was slowly absorbed in the brain of zebrafish after oral administration of paraquat. In addition, paraquat toxicity resulted in behavioral impairments, namely, reduced motor activity and led to abnormal neural activities in zebrafish larvae. This locomotor deficit came with a dysregulation of dopamine synthesis induced by the inhibition of tyrosine hydroxylase activity, which was also indirectly confirmed by molecular modeling studies. Furthermore, short-term exposure to paraquat also caused simultaneous dysregulation of other neurochemistry including cholinergic and serotonergic systems in zebrafish larvae. The present study suggests that this neurotoxicological profiling could be a useful tool for understanding the brain neurochemistry of neurotoxic agents that might be a potential risk to human and environmental health.

Structural Modeling of TRPA1 Ion Channel-Determination of the Binding Site for Antagonists.

TRPA1 is a transmembrane cation channel, one of the most promising targets in the context of respiratory diseases. Its general structure has already been experimentally resolved, but the binding site of TRPA1 antagonists such as HC-030031, a model methylxanthine derivative, remains unknown. The present study aimed to determine the potential binding site of xanthine antagonists and to describe their binding mode, using a molecular modeling approach. This study represents the first attempt to bring together site-directed mutagenesis reports and the latest cryo-EM structure of an antagonist bound to TRPA1. Our research suggests that the core moiety of HC-030031 binds to a pocket formed by the TRP-like domain and the pre-S1, S4, S5 helices of one subunit. The structure, determined by cryo-EM, shows interactions of a core hypoxanthine moiety in the same area of the binding site, sharing the interaction of xanthine/hypoxanthine with Trp-711. Moreover, the predicted binding mode of HC-030031 assumes interaction with Asn-855, a residue demonstrated to be important for HC-030031 recognition in site-directed mutagenesis studies. Our model proved to be advantageous in a retrospective virtual screening benchmark; therefore, it will be useful in research on new TRPA1 antagonists among xanthine derivatives and their bioisosteres.

Potential of Natural Alkaloids From Jadwar (Delphinium denudatum) as Inhibitors Against Main Protease of COVID-19: A Molecular Modeling Approach.

The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (Mpro) has emerged as one of the important drug targets. In this context, the present work explored Jadwar (Delphinium denudatum)–derived natural alkaloids as potential inhibitors against Mpro of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation–based methods. Molecular docking and interaction profile analysis revealed strong binding on the Mpro functional domain with four natural alkaloids viz. panicutine (−7.4 kcal/mol), vilmorrianone (−7.0 kcal/mol), denudatine (−6.0 kcal/mol), and condelphine (−5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the Mpro. Additionally, mechanics/generalized Born/Poisson–Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski’s rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.

Addition of Mercury Causes Quenching of NIR Fluorescence Emission Spectra of a Photoactivatable PAiRFP1 Protein.

Biliverdin (BV) containing far-red light photoactivatable near-infrared fluorescent protein (NIR-FP) named PAiRFP1 has been developed by directed molecular evolution from one bathy bacteriophytochrome of Agrobacterium tumefaciens C58 called Agp2 or AtBphP2. Usually, the fluorescence intensity of the NIR emission spectra of PAiRFP1 tends to increase upon repeated excitation by far-red light. This study aimed at exploring the role of PAiRFP1 and its mutants, such as V386A, V480A, and Y498H, as NIR biosensors for the detection of Hg2+ ions in the buffer solutions. In this study, we used PCR-based site-directed reverse mutagenesis, fluorescence spectroscopy, and molecular modeling approaches on PAiRFP1 and its mutants. It was found that PAiRFP1 and its mutants experienced strong quenching of NIR fluorescence emission spectra upon the addition of different concentrations (0-3μM) of mercuric chloride (HgCl2). We hypothesized that PAiRFP1 and its variants have some potential to be used as NIR biosensors for the in vitro detection of Hg2+ ions in biological media. Moreover, we also hypothesized that PAiRFP1 would be the best tool to use as a NIR biosensor to detect Hg2+ ions in living organisms because of its higher signal-to-noise (SNR) ratio than other infra-red fluorescent proteins.

Investigation of the binding and dynamic features of A.30 variant revealed higher binding of RBD for hACE2 and escapes the neutralizing antibody: A molecular simulation approach

With the emergence of Delta and Omicron variants, many other important variants of SARS-CoV-2, which cause Coronavirus disease-2019, including A.30, are reported to increase the concern created by the global pandemic. The A.30 variant, reported in Tanzania and other countries, harbors spike gene mutations that help this strain to bind more robustly and to escape neutralizing antibodies. The present study uses molecular modelling and simulation-based approaches to investigate the key features of this strain that result in greater infectivity. The protein-protein docking results for the spike protein demonstrated that additional interactions, particularly two salt-bridges formed by the mutated residue Lys484, increase binding affinity, while the loss of key residues at the N terminal domain (NTD) result in a change to binding conformation with monoclonal antibodies, thus escaping their neutralizing effects. Moreover, we deeply studied the atomic features of these binding complexes through molecular simulation, which revealed differential dynamics when compared to wild type. Analysis of the binding free energy using MM/GBSA revealed that the total binding free energy (TBE) for the wild type receptor-binding domain (RBD) complex was −58.25 kcal/mol in contrast to the A.30 RBD complex, which reported −65.59 kcal/mol. The higher TBE for the A.30 RBD complex signifies a more robust interaction between A.30 variant RBD with ACE2 than the wild type, allowing the variant to bind and spread more promptly. The BFE for the wild type NTD complex was calculated to be −65.76 kcal/mol, while the A.30 NTD complex was estimated to be −49.35 kcal/mol. This shows the impact of the reported substitutions and deletions in the NTD of A.30 variant, which consequently reduce the binding of mAb, allowing it to evade the immune response of the host. The reported results will aid the development of cross-protective drugs against SARS-CoV-2 and its variants.

Investigating the binding mechanism of topiramate with bovine serum albumin using spectroscopic and computational methods.

Various spectroscopic techniques involving fluorescence spectroscopy, circular dichroism (CD), and computational approaches were used to elucidate the molecular aspects of interaction between the antiepileptic drug topiramate and the multifunctional transport protein bovine serum albumin (BSA) under physiological conditions. Topiramate quenched BSA fluorescence in a static quenching mode, according to the Stern-Volmer quenching constant (Ksv ) data derived from fluorescence spectroscopy for the topiramate-BSA complex. The binding constant was also used to calculate the binding affinity for the topiramate-BSA interaction. Fluorescence and circular dichroism experiments demonstrate that the protein's tertiary structure is affected by the microenvironmental alterations generated by topiramate binding to BSA. To establish the exact binding site, interacting residues, and interaction forces involved in the binding of topiramate to BSA, molecular modeling and simulation approaches were used. According to the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculations, the average binding energy between topiramate and BSA is -421.05 kJ/mol. Topiramate was discovered to have substantial interactions with BSA, changing the structural dynamic and Gibbs free energy landscape patterns.

A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic, Biochemical, and Molecular Modeling Approaches.

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy.

Antibodies Against Phosphorylcholine Among 60-Year-Olds: Clinical Role and Simulated Interactions.

AimsAntibodies against phosphorylcholine (anti-PC) are implicated as protection markers in atherosclerosis, cardiovascular disease (CVD), and other chronic inflammatory conditions. Mostly, these studies have been focused on IgM. In this study, we determined IgG, IgG1, and IgG2 anti-PC among 60-year-olds.MethodsBased on a 7-year follow-up of 60-year-olds (2,039 men and 2,193 women) from Stockholm County, we performed a nested case-control study of 209 incident CVD cases with 620 age- and sex-matched controls. Anti-PC was determined using ELISA. We predicted the binding affinity of PC with our fully human, in-house-produced IgG1 anti-PC clones (i.e., A01, D05, and E01) using the molecular docking and molecular dynamics simulation approach, to retrieve information regarding binding properties to PC.ResultsAfter adjustment for confounders, IgG and IgG2 anti-PC showed some significant associations, but IgG1 anti-PC was much stronger as a protection marker. IgG1 anti-PC was associated with an increased risk of CVD below 33rd, 25th, and 10th percentile and of stroke below 33rd and 25th, and of myocardial infarction (MI) below 10th percentile. Among men, a strong association with stroke was determined below the 33rd percentile [HR 9.20, CI (2.22–38.12); p = 0.0022]. D05 clone has higher binding affinity followed by E01 and A01 using molecular docking and further have been confirmed during the course of 100 ns simulation. The stability of the D05 clone with PC was substantially higher.ConclusionIgG1 anti-PC was a stronger protection marker than IgG anti-PC and IgG2 anti-PC and also separately for men. The molecular modeling approach helps in identifying the intrinsic properties of anti-PC clones and atomistic interactions with PC.

The influences of cholesterol and AC0107 inhibitor molecules on the amyloid-beta fibrils aggregation in cell membranes: molecular modeling approach

The influences of cholesterol and AC0107 inhibitor molecules on the amyloid-beta fibrils aggregation in cell membranes: molecular modeling approach

Novel perspective into the interaction behavior study of the cyanidin with human serum albumin-holo transferrin complex: Spectroscopic, calorimetric and molecular modeling approaches

We examined the inducement of an interaction between two carrier proteins, human serum albumin (HSA) and human holo transferrin (HTF) within the presence of cyanidinin the form of binary and ternary systems, which was conducted by different spectroscopic, isothermal titration calorimetric (ITC), and molecular dynamics simulation techniques. The results of fluorescence spectroscopy verified the occurrence of this interaction by displaying the regular quenching of emission spectra of proteins as single and complex forms by cyanidin. Moreover, fluorescence emission suggested that, HSA-cyanidin, HTF-cyanidin and (HSA-HTF) cyanidin complexes follows an static mechanism with the binding constants of 8.81 × 104, 3.40 × 104, and 7.10 × 104 M−1, respectively, which were strongly reflected to moderate the affinity of cyanidin to both single and complex forms of proteins. The measured thermodynamic parameters obtained by ITC, determined the necessity of electrostatic forces for binding of cyanidin to HSA and HTF. Besides, obtaining a negative ΔG0 is indicative of spontaneous mode of binding process in both conditions. The different values of thermodynamic parameters of cyanidin binding to the forms of HSA, HTF and HSA-HTF complex clearly proved the similarity in the type of interaction forces between cyanidin and proteins as single and complex forms with various values. The observed changes in synchronous fluorescence results were related to the micro-environment properties of Tyr and Trp residues. The induced alternations in the secondary construction of both proteins were confirmed through the outcomes of quantitative analysis performed by circular dichroism spectroscopy (CD) techniques. FRET theory was exerted to calculate, the existing distance across the donor and acceptor, which were reported to be 1.85 nm, 1.97 nm, and 1.91 nm for the cases of HSA-cyanidin, HTF-cyanidin and (HSA-HTF) cyanidin complexes, respectively. Molecular displacement and protein–ligand docking simulations confirmed the binding of cyanidin to HSA and HTF through the binary and ternary systems.

Novel allosteric inhibitor to target drug resistance in EGFR mutant: molecular modelling and free energy approach

ABSTRACT Anticancer therapy targets Tyrosine kinase (TK) to inhibit signal transduction pathway that regulate various physiological and biochemical processes. Mutation in and around the catalytic domain may lead to conformational changes and activity. The first identified mutation leading to resistance against tyrosine kinase inhibitor (TKI) was observed when Thr at 790 replaced to Met in Epidermal Growth Factor Receptor (EGFR). Third generation EGFR-TKIs bind irreversibly to the Cysteine 797, (ATP-binding pocket). Mutation of Cys 797 to Ser residue (EGFRC797S) causes resistance to third generation TKI. The present study explores allosteric inhibitor of EGFRT790M+C797S mutant TK by molecular modelling techniques using 3,92,945 compounds of Zinc database. Molecular docking study revealed that ZINC000072404720 have similar binding pattern and MM/GBSA free energy as known allosteric inhibitor EAI045. RMSD of EGFRT790M+C797S bound to EAI045 and ZINC000072404720 were quite similar and in acceptable range. Hydrogen bonds after 150ns simulation was observed between Lys 745 and Asp 855 with EAI045 and novel inhibitor showed hydrogen bonding with Lys 745, Leu 788, Thr 854, Asp 855, Phe 856. MM/GBSA free energy was better (-84.09 Kcal/mol) known inhibitor EAI045b (-65.95 Kcal/mol). ZINC000072404720 fulfils drug likeliness property and did not violate Lipinski’s rule of five.

Investigating the novel acetonitrile derivatives as potential SARS-CoV-2 main protease inhibitor using molecular modeling approach

The COVID-19 is declared a pandemic by World Health Organization (WHO). It causes respiratory illness which leads to oxygen deficiency; it has affected millions of lives all around the globe. It has also been observed that people with diabetes condition are more likely to have severe symptoms when infected with the SARS-CoV2. So, continued efforts are being taken to design and discover potential anti-covid drugs. Earlier, a study reveals that the acetonitrile (2-phenyl-4H-benzopyrimedo [2,1-b]-thiazol-4-yliden) derivatives have potential anti-diabetic activity. Hence, drugs repurpose approach was used to identify the potential acetonitrile derivative targeting the main protease of SARS-CoV2. Here, ADMET, molecular docking, and molecular dynamics simulation techniques were employed, to identify potential acetonitrile compounds against the main protease. The acetonitrile compounds (A to M) show the drug-likeness properties. Next, the molecular docking and dynamics simulation study reveals that acetonitrile compounds A, F, G, and L show a higher binding affinity and have an effect on the structure and dynamics of the main protease. Furthermore, binding energy calculations reveal that the acetonitrile derivative F has a higher binding affinity with the main protease and derivative L has a lower binding affinity with the main protease. The binding affinity of acetonitrile derivatives decreases in the order of F > A > G > L with the main protease. Thus, our computational modeling study provides valuable structural and energetic information of interaction of potential acetonitrile derivatives with the main protease which could be further used as potential lead molecules against the SARS-CoV2. Communicated by Ramaswamy H. Sarma

The Molecular Basis of the Effect of Temperature on the Structure and Function of SARS-CoV-2 Spike Protein

The remarkable rise of the current COVID-19 pandemic to every part of the globe has raised key concerns for the current public healthcare system. The spike (S) protein of SARS-CoV-2 shows an important part in the cell membrane fusion and receptor recognition. It is a key target for vaccine production. Several researchers studied the nature of this protein under various environmental conditions. In this work, we applied molecular modeling and extensive molecular dynamics simulation approaches at 0°C (273.15 K), 20°C (293.15 K), 40°C (313.15 K), and 60°C (333.15 K) to study the detailed conformational alterations in the SARS-CoV-2 S protein. Our aim is to understand the influence of temperatures on the structure, function, and dynamics of the S protein of SARS-CoV-2. The structural deviations, and atomic and residual fluctuations were least at low (0°C) and high (60°C) temperature. Even the internal residues of the SARS-CoV-2 S protein are not accessible to solvent at high temperature. Furthermore, there was no unfolding of SARS-CoV-2 spike S reported at higher temperature. The most stable conformations of the SARS-CoV-2 S protein were reported at 20°C, but the free energy minimum region of the SARS-CoV-2 S protein was sharper at 40°C than other temperatures. Our findings revealed that higher temperatures have little or no influence on the stability and folding of the SARS-CoV-2 S protein.

Crystal structure of Acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus and insights into the substrate-binding through in silico mutagenesis and biophysical investigations

Acetyl-CoA carboxylase (ACC) is crucial for polyketides biosynthesis and acts as an essential metabolic checkpoint. It is also an attractive drug target against obesity, cancer, microbial infections, and diabetes. However, the lack of knowledge, particularly sequence-structure function relationship to narrate ligand-enzyme binding, has hindered the progress of ACC-specific therapeutics and unnatural “natural” polyketides. Structural characterization of such enzymes will boost the opportunity to understand the substrate binding, designing new inhibitors and information regarding the molecular rules which control the substrate specificity of ACCs. To understand the substrate specificity, we determined the crystal structure of AccB (Carboxyl-transferase, CT) from Streptomyces antibioticus with a resolution of 2.3 Å and molecular modeling approaches were employed to unveil the molecular mechanism of acetyl-CoA recognition and processing. The CT domain of S. antibioticus shares a similar structural organization with the previous structures and the two steps reaction was confirmed by enzymatic assay. Furthermore, to reveal the key hotspots required for the substrate recognition and processing, in silico mutagenesis validated only three key residues (V223, Q346, and Q514) that help in the fixation of the substrate. Moreover, we also presented atomic level knowledge on the mechanism of the substrate binding, which unveiled the terminal loop (500–514) function as an opening and closing switch and pushes the substrate inside the cavity for stable binding. A significant decline in the hydrogen bonding half-life was observed upon the alanine substitution. Consequently, the presented structural data highlighted the potential key interacting residues for substrate recognition and will also help to re-design ACCs active site for proficient substrate specificity to produce diverse polyketides.