Molecular Mechanics Poisson-Boltzmann Research Articles

Drug repurposing for schistosomiasis: molecular docking and dynamics investigations

Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or oxamniquine but there are reported cases of treatment failures due to resistance or tolerance. Again, derivatives of praziquantel and oxamniquine have not shown significant activities than their parent compounds. The study predicted approved drugs with possible antischistosomal activities. Four schistosomal drug targets were obtained from Protein Data Bank and six hundred and twelve (612) approved drugs including their isomers were selected based on their Molinspiration® bioscore similarities with reference compounds (praziquantel, oxamniquine, [(2S,3S,4S,5S,6S)-3,4,5-triacetyloxy-6-sulfanyloxan-2-yl] methyl acetate, [propylamino-3-hydroxy-buta-1,4-dionyl]-isoleucylproline). The selected drugs and drug targets were obtained and prepared for molecular docking simulations. The molecular docking simulations were performed using AutoDockvina®-1.1.2 after validation of docking protocols while molecular dynamics simulations were performed with GROMACS-4.5.5. The binding energies were calculated using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area). Tolmetin was predicted as potential antischistosomal drug with binding energies of −231.064 ± 18.550 and −338.636 ± 36.900 KJ/mol for sulfotransferase and thioredoxin glutathione reductase (TGR) respectively. Also diflunisal was predicted as potential antischistosomal drug with binding energies of −168.641 ± 20.370 and −290.117 ± 43.800 KJ/mol for sulfotransferase and TGR respectively. Non-covalent interactions and conformational changes were responsible for molecular recognitions and specificities and average bond measurement showed that carboxylic functional groups in diflunisal and tolmetin may interact covalently with -SH group of Cys159 in TGR. Confirmation of covalent interactions and in vitro validations are recommended. Communicated by Ramaswamy H. Sarma

A Computational Study to Identify Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro) from Eucalyptus Active Compounds

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found to be a severe threat to global public health in late 2019. Nevertheless, no approved medicines have been found to inhibit the virus effectively. Anti-malarial and antiviral medicines have been reported to target the SARS-CoV-2 virus. This paper chose eight natural eucalyptus compounds to study their binding interactions with the SARS-CoV-2 main protease (Mpro) to assess their potential for becoming herbal drugs for the new SARS-CoV-2 infection virus. In-silico methods such as molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics Poisson Boltzmann Surface Area (MM/PBSA) analysis were used to examine interactions at the atomistic level. The results of molecular docking indicate that Mpro has good binding energy for all compounds studied. Three docked compounds, α-gurjunene, aromadendrene, and allo-aromadendrene, with highest binding energies of −7.34 kcal/mol (−30.75 kJ/mol), −7.23 kcal/mol (−30.25 kJ/mol), and −7.17 kcal/mol (−29.99 kJ/mol) respectively, were simulated with GROningen MAchine for Chemical Simulations (GROMACS) to measure the molecular interactions between Mpro and inhibitors in detail. Our MD simulation results show that α-gurjunene has the strongest binding energy of −20.37 kcal/mol (−85.21 kJ/mol), followed by aromadendrene with −18.99 kcal/mol (−79.45 kJ/mol), and finally allo-aromadendrene with −17.91 kcal/mol (−74.95 kJ/mol). The findings indicate that eucalyptus may be used to inhibit the Mpro enzyme as a drug candidate. This is the first computational analysis that gives an insight into the potential role of structural flexibility during interactions with eucalyptus compounds. It also sheds light on the structural design of new herbal medicinal products against Mpro.

Molecular dynamics simulations of the interactions between triose phosphate isomerase and sulfonamides

Malaria is a disease with debilitating health and negative economic impacts in regions at high risk of infection. Parasitic resistance and side effects of current antimalarial drugs are major setbacks to the successful campaigns that have reduced malaria incidence by 40% in the last decade. The parasite’s dependence on glycolysis for energy requirements makes pathway enzymes suitable targets for drug development. Specifically, triose phosphate isomerase (TPI) from Plasmodium falciparum (pTPI) and human (hTPI) cells show striking structural features that can be used in development of new antimalarial agents. In this study MD simulations were used to characterize binding sites on hTPI and pTPI interactions with sulfonamides. The molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) method was used to estimate the interaction energies of four sulfonamide-TPI docked complexes. A unique combination of key residues at the dimer interface of pTPI is responsible for the observed selective affinity to pTPI compared to hTPI. The representative sulfonamide; 4-amino-N-(3,5-dimethylphenyl)-3-fluorbenzenesulfonamide (sulfaE) shows a strong affinity with pTPI (dimer interface, −42.91 kJ/mol and active site region, −71.62 kJ/mol), hTPI (dimer interface, −41.32 kJ/mol and active site region, −84.40 kJ/mol). Strong and favorable Van der Waals interactions and increases in non-polar solvation energies explain the difference in affinity between pTPI with sulfaE compared to hTPI at the dimer interface. This is an indication that the dimer interface of TPI glycolytic enzyme is vital for development of sulfonamide based antimalarial drugs.

Role of Thermolysin in Catalytic-Controlled Self-Assembly of Fmoc-Dipeptides

In recent years, short peptide self-assembled materials, prepared under the control of the thermolysin catalyst, have been investigated extensively and shown to acquire various morphologies and fun...

Computational binding study with α7 nicotinic acetylcholine receptor of Anvylic-3288: an allosteric modulator

ABSTRACT Nicotinic receptors are ligand-gated ion channels, involved in the generation of action potential in post synaptic membrane and motor endplate. The α7 Nicotinic Acetylcholine Receptor (nAChR) is a class of nicotinic receptor involved in cognition. It is distributed in hippocampus, thalamus, sensory and information processing regions of the brain. The receptor is implicated in various diseases, including Alzheimer’s disease, Parkinsonism, Schizophrenia, Autism, Rett syndrome etc. Therefore, targeting the modulation of the receptor would be advantageous. Positive allosteric modulators (PAMs) potentiate the response i.e. peak current of the receptor. Type I allosteric modulator, Anvylic-3288 (AVL-3288), increases peak current without altering the response of α7-nAChR upon acetylcholine binding. In present study, in silico approach was used to identify the plausible binding model of AVL-3288 involved in modulation. Docking study displayed that a1 binding modes had better binding energies than the t1 and v1 modes. The MD (Molecular Dynamics) simulation produced stable complex for a1 pose, binding to agonist subpocket, with α7-nAChR having protein and ligand RMSD (Root Mean Square Deviation) in the acceptable limits, and comparable to MM/PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) results.

De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study

In the present study, pharmacoinformatics paradigms include receptor-based de novo design, virtual screening through molecular docking and molecular dynamics (MD) simulation are implemented to identify novel and promising HIV-1 integrase inhibitors. The de novodrug/ligand/molecule design is a powerful and effective approach to design a large number of novel and structurally diverse compounds with the required pharmacological profiles. A crystal structure of HIV-1 integrase bound with standard inhibitor BI-224436 is used and a set of 80,000 compounds through the de novo approach in LigBuilder is designed. Initially, a number of criteria including molecular docking, in-silico toxicity and pharmacokinetics profile assessments are implied to reduce the chemical space. Finally, four de novo designed molecules are proposed as potential HIV-1 integrase inhibitors based on comparative analyses. Notably, strong binding interactions have been identified between a few newly identified catalytic amino acid residues and proposed HIV-1 integrase inhibitors. For evaluation of the dynamic stability of the protein-ligand complexes, a number of parameters are explored from the 100 ns MD simulation study. The MD simulation study suggested that proposed molecules efficiently retained their molecular interaction and structural integrity inside the HIV-1 integrase. The binding free energy is calculated through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach for all complexes and it also explains their thermodynamic stability. Hence, proposed molecules through de novo design might be critical to inhibiting the HIV-1 integrase.

How Does the Mono-Triazole Derivative Modulate Aβ42 Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations.

Clinical studies have identified that abnormal self-assembly of amyloid-β (Aβ) peptide into toxic fibrillar aggregates is associated with the pathology of Alzheimer’s disease (AD). The most acceptable therapeutic approach to stop the progression of AD is to inhibit the formation of β-sheet-rich structures. Recently, we designed and evaluated a series of novel mono-triazole derivatives 4(a–x), where compound 4v was identified as the most potent inhibitor of Aβ42 aggregation and disaggregates preformed Aβ42 fibrils significantly. Moreover, 4v strongly averts the Cu2+-induced Aβ42 aggregation and disaggregates the preformed Cu2+-induced Aβ42 fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aβ42 aggregation by 4v and disaggregation of preformed Aβ42 fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aβ42 monomer and a pentameric protofibril structure of Aβ42 in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the Aβ42 monomer and chains D and E of the Aβ42 protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the Aβ42 monomer into the aggregation-prone β-sheet conformation. The binding free energy calculated by the molecular mechanics Poisson–Boltzmann surface area method revealed an energetically favorable process with ΔGbinding = −44.9 ± 3.3 kcal/mol for the Aβ42 monomer–4v complex. The free energy landscape analysis highlighted that the Aβ42 monomer–4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aβ42 monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and π–π interactions with Phe19 (chain D) of the Aβ42 protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aβ42 protofibril showed the maximum contribution in the binding free energy. The decreased binding affinity and residue–residue contacts between chains D and E of the Aβ42 protofibril in the presence of 4v indicate destabilization of the Aβ42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the Aβ42 monomer and persuades a destabilization in the protofibril structure of Aβ42. The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.

Structure-based identification of natural compound inhibitor against M. tuberculosis thioredoxin reductase: insight from molecular docking and dynamics simulation

Antioxidant systems of M. tuberculosis (Mtb) play an important role in providing resistance in the hostile environment of mononuclear phagocytes. Thioredoxin system is a known antioxidant system that consists of three copies of thioredoxins (Trxs) and a single copy of thioredoxin reductase (TrxR). TrxR has been validated as an essential gene known to be involved in the reduction of peroxides, dinitrobenzenes and hydroperoxides, and is crucial in maintaining the survival of Mtb in macrophages. Recently, it has been demonstrated to be a druggable target. In this study, molecular docking was applied to screen more than 20,000 natural compounds from the Traditional Chinese Medicine database. Theoretical calculation of ΔGbinding by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) methods indicated two top-hit compounds that bind with a high affinity to the allosteric site, consisting of a hinge region, of TrxR. Further, stability and binding analysis of both compounds were carried out with molecular dynamics simulation. An analysis of conformational variation by principal component analysis (PCA) and protein contact network (PCN) uncovered the conformational changes in the compound-bound forms of protein. The NADPH domain formed many new interactions with the FAD domain in the compound-bound form, signifying that the binding may render an effect on the protein structure and function. Our results suggest that these two compounds could potentially be used for structure-based lead inhibitors against TrxR. The inhibitor selected as lead compound will be used further as a scaffold to optimize as novel anti-tuberculosis therapeutic. Communicated by Ramaswamy H. Sarma

Molecular docking and dynamics simulations studies of OmpATb identifies four potential novel natural product-derived anti-Mycobacterium tuberculosis compounds

The outer membrane protein A (OmpATb) of Mycobacterium tuberculosis is a virulence factor that neutralizes the host pH to impede the uptake of hydrophilic antitubercular drugs. Identifying natural compounds with the potential to inhibit OmpATb could allow circumvention of the porin-like activities of OmpATb. Four potential leads comprising ZINC000003958185, ZINC000000157405, ZINC000000001392 and ZINC000034268676 were obtained by virtual screening of 6394 diverse natural products. Characterization of the binding interactions of the potential leads with OmpATb revealed nine critical residues comprising ARG86, LEU110, LEU113, LEU114, ALA115, PHE142, SER145, VAL146, and PHE151. Molecular dynamics simulations also revealed very stable protein-lead complexes. Most residues contributed lower binding energies to the overall molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energies of the interactions between the molecules and OmpATb protein. Induced Fit Docking (IFD) of the compounds regenerated poses of the molecular docking using AutoDock Vina. These molecules could be starting templates for designing inhibitors to bypass the pore mediating activities of OmpATb. Based on structural similarity, ZINC000034268676 was suggested as a potential scaffold for designing efflux pump inhibitors of the gate mediating activities of OmpATb and may enhance the uptake of hydrophilic drugs to reduce the duration time of tuberculosis treatment. Furthermore, structurally similar compounds available in the DrugBank database with a similarity threshold of 0.7 have been reported to exhibit antitubercular and anti-mycobacterial activities. These biomolecules can be further characterized experimentally to corroborate their antitubercular activity. Also, the skeletons of the molecules can be adopted as sub-structures for the design of future anti-mycobacterial drugs.

Screening and analysis of bioactive food compounds for modulating the CDK2 protein for cell cycle arrest: Multi-cheminformatics approaches for anticancer therapeutics

The cyclin-dependent kinase-2 (CDK2) belongs to the protein kinase family and its overexpression leads to an unusual regulation of cell-cycle which directly linked with hyperproliferation in many cancer cell types. CDK2 activation spontaneously promotes the cell cycle progression and also involved in a large number of cellular processes including cell cycle regulation, DNA replication, DNA damage response and apoptotic pathways, therefore targeting the CDK2 can be reemerged as a therapeutic boulevard to restrain cancer cell proliferation. For the last two decades, emerging evidences suggested that CDK2 inhibition draws out some antitumor/anticancer activity, which has driven the research possibility for developing next-generation newer or cost-effective inhibitors with greater specificity to CDK2. In the current work, compounds from the FooDB - a world’s largest food constituents database was retrieved and curated and followed by multi-pharmacoinformatics approaches adopted to find out potential CDK2 inhibitors. The curated dataset was considered for screening through “Virtual Screening Workflow” (VSW) employed in Schrödinger suite. The numbers of cost-effective food constituents were reduced by removing low potential molecules in terms of interaction affinity and further explored for pharmacokinetics analysis. Based on strong binding interaction profiles with the lowest binding interactions affinity and energy values, four food compounds were proposed as CDK2 inhibitors. A number of key analyzing parameters from molecular dynamics (MD) simulations studies were successfully substantiated that all four proposed food compounds can act as CDK2 inhibitors based on their proficient structural and molecular interactions integrity with CDK2 protein following in the active site cavity. Furthermore, the binding free energy was calculated using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach from the entire trajectory frames derived in MD simulation revealed strong interaction affinity. The binding free energy was found to be in the range of −991.831 to −210.452 kJ/mol. High binding free energy was undoubtedly explained that all molecules possess strong affection towards CDK2. Hence, proposed molecules may be crucial to stop the hyperproliferation in cancer cells subjected to experimental validation.

Protein ligand interaction analysis against new CaMKK2 inhibitors by use of X-ray crystallography and the fragment molecular orbital (FMO) method

CaMKK2 (calcium/calmodulin dependent protein kinase kinase 2) is a serine/threonine protein kinase that regulates phosphorylation of CaM kinases (CaMKs) such as CaMKI, CaMKIV, and AMP-activated protein kinase (AMPK). From a pathological perspective, CaMKK2 plays a role in obesity, diabetes, and prostate cancer. Therefore, CaMKK2 is an attractive target protein for drug design. Here, we tried to find new CaMKK2 inhibitors by using ligand-based and structure-based drug design approaches. From the in silico hit compounds, we identified new inhibitors by using a CaMKK2 kinase assay. We solved X-ray crystallography structures of the CaMKK2–inhibitor complexes and performed Fragment Molecular Orbital (FMO) calculations to analyze the protein–ligand interactions, identify the key residues in inhibitor binding, and quantitatively measure their contribution. We experimentally determined five CaMKK2–inhibitor structures and calculated the binding energies of the inhibitors by the FMO method plus MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach. The results showed a high correlation (R = −0.89) between experimentally measured inhibitory activity (pIC50) and the predicted ligand binding energy. We then quantitatively evaluated the contribution of each binding site residue in CaMKK2 by the IFIE (Inter-fragment Interaction Energy)/PIEDA (Pair Interaction Energy Decomposition Analysis) method. The IFIE values indicated that Lys194 and Glu236, which formed hydrogen bonds with the carboxylate groups of the inhibitors, were key residues for ligand binding. PIEDA revealed that the dispersion interaction of inhibitors with hydrophobic residues, such as Ile171, Phe267, and Leu319, contributed highly to ligand binding; we considered that this was due to CH-π interactions with methoxy groups and/or aromatic rings contained in our CaMKK2 inhibitor. These results from the quantitative interaction analysis by the FMO method are useful not only for future CaMMK2 inhibitor development but for application of the FMO method to in silico drug design.

Ligand Binding Mechanism and Its Relationship with Conformational Changes in Adenine Riboswitch.

Riboswitches are naturally occurring RNA aptamers that control the expression of essential bacterial genes by binding to specific small molecules. The binding with both high affinity and specificity induces conformational changes. Thus, riboswitches were proposed as a possible molecular target for developing antibiotics and chemical tools. The adenine riboswitch can bind not only to purine analogues but also to pyrimidine analogues. Here, long molecular dynamics (MD) simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) computational methodologies were carried out to show the differences in the binding model and the conformational changes upon five ligands binding. The binding free energies of the guanine riboswitch aptamer with C74U mutation complexes were compared to the binding free energies of the adenine riboswitch (AR) aptamer complexes. The calculated results are in agreement with the experimental data. The differences for the same ligand binding to two different aptamers are related to the electrostatic contribution. Binding dynamical analysis suggests a flexible binding pocket for the pyrimidine ligand in comparison with the purine ligand. The 18 μs of MD simulations in total indicate that both ligand-unbound and ligand-bound aptamers transfer their conformation between open and closed states. The ligand binding obviously affects the conformational change. The conformational states of the aptamer are associated with the distance between the mass center of two key nucleotides (U51 and A52) and the mass center of the other two key nucleotides (C74 and C75). The results suggest that the dynamical character of the binding pocket would affect its biofunction. To design new ligands of the adenine riboswitch, it is recommended to consider the binding affinities of the ligand and the conformational change of the ligand binding pocket.

Genetic diversity and in silico evidence of target-site mutation in the EPSPS gene in endowing glyphosate resistance in Eleusine indica (L.) from Malaysia

Glyphosate-resistant populations of Eleusine indica are widespread in several states of Malaysia. A whole-plant bioassay confirmed that eight out of the 17 populations tested were resistant to glyphosate at double the recommended rate of 2.44 kg ha−1. Screening with allele-specific PCR (AS-PCR) revealed that resistant plants contained an EPSPS gene with either the homozygous S/S-106 or the heterozygous P/S-106 alleles. All susceptible plants contained only the homozygous P/P-106 allele. In addition, DNA sequences of the full-length EPSPS gene from one susceptible (SB) and four resistant (R2, R6, R8 and R11) populations revealed an amino acid substitution of T102I in all the resistant plants, while another substitution of P381L was only found in resistant populations R6 and R11. The significance of the P381L mutation was examined by Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and residue interaction network (RIN) analyses, which suggests the P381L mutation may contribute to resistance. Mutations at 102 and 106 occur widely in the EPSPS gene of glyphosate-resistant E. indica populations from Malaysia with the TIPS mutation. In addition, the P381L mutation could also contribute to resistance.

Investigation of noncovalent interactions between peptides with potential intrinsic sequence patterns by mass spectrometry.

The conformation of a protein largely depends on the interactions between peptides. Specific and intrinsic sequence peptide patterns, such as DNA double helix backbones, may be present in proteins. A computational statistical deep learning method has supported this assumption, but it has not been experimentally proven. Mass spectrometry, as a fast and accurate experimental method, could be used to evaluate the interaction of biomolecules. The results would be of great value for further study of the mechanism of protein folding. Several potential intrinsic peptides were chosen by the deep learning method, including seven groups of pentapeptides and five groups of nonapeptides. The noncovalent interactions between mixed polypeptides were investigated by electrospray ionization mass spectrometry (ESI-MS) in full-scan and collision-induced dissociation (CID) modes. Molecular dynamics and molecular mechanics Poisson-Boltzmann surface area (MD-MM/PBSA) analyses were also performed to support the results. The ESI-MS spectra showed that 11 of the 12 groups of mixed polypeptides formed binary and ternary complexes with relatively high stability. The binding between nonapeptide groups was stronger than that between pentapeptide groups according to the relative intensity. The binding energies calculated by the MM/PBSA binding energy tool also provided strong evidence for the combination of the complexes. Electrostatic interactions, hydrophobic interactions, and van der Waals forces were thought to stabilize the complexes according to the binding models. The results implied the formation of stable complexes between polypeptides and identified their noncovalent interactions, proving that specific sequences and combinations with relatively strong binding ability exist in potential intrinsic sequences of peptides in protein structures.

Probing Carbon Utilization of Cordyceps militaris by Sugar Transportome and Protein Structural Analysis.

Beyond comparative genomics, we identified 85 sugar transporter genes in Cordyceps militaris, clustering into nine subfamilies as sequence- and phylogenetic-based functional classification, presuming the versatile capability of the fungal growths on a range of sugars. Further analysis of the global gene expression patterns of C. militaris showed 123 genes were significantly expressed across the sucrose, glucose, and xylose cultures. The sugar transporters specific for pentose were then identified by gene-set enrichment analysis. Of them, the putative pentose transporter, CCM_06358 gene, was highest expressed in the xylose culture, and its functional role in xylose transport was discovered by the analysis of conserved structural motifs. In addition, a battery of molecular modeling methods, including homology modeling, transport pathway analysis, residue interaction network combined with molecular mechanics Poisson–Boltzmann surface area simulation (MM-PBSA), was implemented for probing the structure and function of the selected pentose transporter (CCM_06358) as a representative of sugar transportome in C. militaris. Considering the network bottlenecks and structural organizations, we further identified key amino acids (Phe38 and Trp441) and their interactions with other residues, contributing the xylose transport function, as verified by binding free energy calculation. The strategy used herein generated remarkably valuable biological information, which is applicable for the study of sugar transportome and the structure engineering of targeted transporter proteins that might link to the production of bioactive compounds derived from xylose metabolism, such as cordycepin.

The search for peptide deformylase inhibitor from Indonesian Medicinal Plant Database: an in-silico investigation

The peptide deformylase protein (PDF) has emerged as a promising target for the discovery of novel antibiotics with a novel mechanism of action. The current investigation was aimed at identifying potential inhibitor of PDF by using structure-based pharmacophore modelling. The pharmacophore hypothesis consisted of one hydrophobic, one negative ionizable, and one hydrogen bond donor features which were built using the structure of cognate ligand of PDF (BB2). Further, the pharmacophore model was validated and used to screen hit molecule against Indonesian Medicinal Plant Database and retrieved 32 hit molecules. All hit molecules were docked to PDF and four best molecules were subjected for 50-ns molecular dynamics (MD) simulation. MD simulation confirmed the docked poses of ligand as indicated by the RMSD and RMSF values. Prediction of affinities employing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method revealed that quercetin 3-(6''-malonylneohesperidoside) had a comparable affinity with that of BB2, which indicated its potential as a novel herbal-based PDF inhibitor.

Identification of a novel binding mechanism of Quinoline based molecules with lactate dehydrogenase of Plasmodium falciparum

The deadliest disease caused by the Plasmodium species is malaria. Among other species, the infection caused by Plasmodium falciparum (Pf) is life-threatening. The biological function and three-dimensional structure of PfLDH and human LDH are very similar. Any treatment aiming to inhibit the PfLDH can also affect the activity of human LDH. This study aims to identify molecules that show high selectivity for PfLDH without having a profound effect on the activity of human LDH. In this study, 30 in-house synthesized Quinolines based molecules were docked with both PfLDH and human LDH. Based on molecular docking results, molecules 3j, 4b, 4h, 4m were showed selectivity towards PfLDH. All the four molecules had better binding affinity, ligand efficiency, lipophilic ligand efficiency, and torsion than Chloroquine (referenced inhibitor). Further, molecular dynamics (MD) simulations and molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations were carried out to validate the docking results and to compare the stability of selected complexes against the complex with Chloroquine. MD simulations showed stable dynamic behavior of all the selected molecules in comparison to Chloroquine. Finally, on the basis of MM-PBSA analysis, molecule 3j was revealed novel binding mechanism and was selected as the potent and selective inhibitor of PfLDH.Communicated by Ramaswamy H. Sarma

Computational Study of Encapsulation of Polyaromatic Hydrocarbons by Endo-Functionalized Receptors in Nonpolar Medium.

Polycyclic aromatic hydrocarbons (PAHs) constitute a large group of organic pollutants produced from either natural or artificial sources during the incomplete combustion of fossil fuels or derived from various industrial processes (such as refinery processes of crude petroleum). They are seriously hazardous to human health, and removing them is of major importance. The complexation likeliness with and selective recognition of PAH guests by endo-functionalized molecular tube hosts (host-abu and host-abtu) in a nonpolar medium are investigated using classical molecular dynamics simulation and quantum calculation to probe the factors and the molecular mechanism involved in complexation processes. We examine the role of different guest molecules in the structural changes of hosts, a prelude to van der Waals interactions and binding free energy in the complexation process. These types of host-guest interactions depend on various factors. We find that (i) both the host molecules (host-abtu and host-abu) interact with the guest π-electron cloud almost equally and (ii) these interactions also depend on the molecular size of PAHs. The larger the nonpolar surface area of PAHs, the greater the interactions with the host, and the more extensive the π-electron cloud of the guest, the stronger the interactions. The linear PAHs interact more strongly than isomeric branched/curved PAHs, and the presence of heteroatoms on PAHs decreases the interactions with the host by creating repulsion between the lone pairs of heteroatoms and the π-electron cloud of the host. Noncovalent van der Waals interactions and N-H···π interactions dominate the high affinities of PAHs toward host-abu and host-abtu. The potential of mean force and molecular mechanics Poisson-Boltzmann surface area calculations reveal that all host-guest complexes are energetically stable.

Molecular Interactions of Renin with Chikusetsusaponin IV and Momordin IIc

The paper dealt with the molecular mechanism for the binding sites and driving forces of renin with chikusetsusaponin IV and momordin IIc by means of molecular docking and free energy calculation based on the crystal structure. The result showed that renin and the saponins fit well. As shown by LigPlot + software analyzing the hydrogen bonding and hydrophobic effect between renin and the saponins, the amino acid residues such as Ser230, Tyr85, and Tyr201 form the hydrogen bonds, with S3sp, S3, and S2′ being the active pockets. In addition, there are relatively strong hydrophobic interactions of renin with saponins in S3sp, S3, S2, S1, S1′, and S2′, with Gly228, Val36, Ala229, Gln19, Met303, Gln135, Ser41, Ile137, Asp38, Arg82, and Tyr83 being the key amino acids. The dynamics reached equilibration after about 1000 ps simulation with average root-mean-square deviations of 0.222 nm and 0.217 nm. The molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) yielded −1.10812 kcal/mol and −39.0587 kcal/mol total binding energy for the two complexes, respectively, which were primarily contributed by electrostatic and van der Waals interaction energies, and the binding was strongly unfavored by polar solvation energy, a further confirmation that momordin IIc has stronger hydrogen bonding and hydrophobic effect in the inhibition of renin than the chikusetsusaponin IV.

Identification of potential drug-like molecules for inhibition of the inflammatory activity of cyclooxygenase-2

Inflammation plays a pivotal role in all stages of atherosclerosis and therefore targeting the key enzymes of this pathway may help in ameliorating the disease progression. The current study is aimed to identify small lead molecules as a promising inhibitor for the cyclooxygenase-2 (COX-2), a therapeutically important protein involved in the prostaglandin biosynthesis pathway and a key player in driving the inflammatory atherogenic progression. Herein, we have used extensive computational methods such as virtual screening, protein–ligand docking, molecular dynamics simulation and binding free energy analysis. Out of 2500 molecules, 1408 compounds have favourable drug-like properties. ZINC72348892 showed GOLD fitness score of 86.38 with COX-2 and established two hydrogen bonds with Phe519 and mostly hydrophobic interactions. The second lead ZINC72295579 showed GOLD fitness score of 84.07 with COX-2 and exhibited four hydrogen bonds with His90, Tyr356, Tyr386 and Ala528. Both the lead compounds exhibit high binding affinity for COX-2 compared with COX-1 isoenzyme. Further, the lead molecules showed a favourable Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) Gibbs binding free energy lower compared to the control. Van der Waal energy is the predominant component driving the interaction of the lead molecules with COX-2. Essential dynamics and entropy calculation further confirmed the structural rigidity and compactness of the protein upon binding of the lead molecules. Thus our findings suggest that ZINC72348892 and ZINC72295579 as promising lead molecules for inhibition of COX-2 and which would provide alternative chemotypes in the drug discovery pipeline for the treatment of cardiovascular diseases.AbbreviationsCVDsCardiovascular diseasesCOXCyclooxygenaseMDMolecular dynamicsMM/PBSAMolecular mechanics Poisson–Boltzmann surface areaROFRule of fiveNVTNumber of particles, volume and temperatureNPTNumber of particles, pressure and temperatureRMSDRoot mean square deviationRMSFRoot mean square fluctuationSASASolvent accessible surface areaRgRadius of gyrationPCAPrincipal component analysisEDEssential dynamicsNHBsNumber of hydrogen bondsCommunicated by Ramaswamy H. Sarma