CD4-gp120 interaction interface - a gateway for HIV-1 infection in human: molecular network,modeling and docking studies

The major causative agent for Acquired Immune Deficiency Syndrome (AIDS) is Human Immunodeficiency Virus-1 (HIV-1). HIV-1 is a predominant subtype of HIV which counts on human cellular mechanism virtually in every aspect of its life cycle. Binding of viral envelope glycoprotein-gp120 with human cell surface CD4 receptor triggers the early infection stage of HIV-1. This study focuses on the interaction interface between these two proteins that play a crucial role for viral infectivity. The CD4–gp120 interaction interface has been studied through a comprehensive protein–protein interaction network (PPIN) analysis and highlighted as a useful step towards identifying potential therapeutic drug targets against HIV-1 infection. We prioritized gp41, Nef and Tat proteins of HIV-1 as valuable drug targets at early stage of viral infection. Lack of crystal structure has made it difficult to understand the biological implication of these proteins during disease progression. Here, computational protein modeling techniques and molecular dynamics simulations were performed to generate three-dimensional models of these targets. Besides, molecular docking was initiated to determine the desirability of these target proteins for already available HIV-1 specific drugs which indicates the usefulness of these protein structures to identify an effective drug combination therapy against AIDS.     

Development of small-molecule probes that selectively kill cells induced to express mutant RAS

Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.     

Identification of Phosphoribosyl-AMP cyclohydrolase,as drug target and its inhibitors in Brucella melitensis bv. 1 16M using metabolic pathway analysis

Brucella melitensis is a pathogenic Gram-negative bacterium which is known for causing zoonotic diseases (Brucellosis). The organism is highly contagious and has been reported to be used as bioterrorism agent against humans. Several antibiotics and vaccines have been developed but these antibiotics have exhibited the sign of antibiotic resistance or ineffective at lower concentrations, which imposes an urgent need to identify the novel drugs/drug targets against this organism. In this work, metabolic pathways analysis has been performed with different filters such as non-homology with humans, essentially of genes and choke point analysis, leading to identification of novel drug targets. A total of 18 potential drug target proteins were filtered out and used to develop the high confidence protein–protein interaction network The Phosphoribosyl-AMP cyclohydrolase (HisI) protein has been identified as potential drug target on the basis of topological parameters. Further, a homology model of (HisI) protein has been developed using Modeller with multiple template (1W6Q (48%), 1ZPS (55%), and 2ZKN (48%)) approach and validated using PROCHECK and Verify3D. The virtual high throughput screening (vHTS) using DockBlaster tool has been performed against 16,11,889 clean fragments from ZINC database. Top 500 molecules from DockBlaster were docked using Vina. The docking analysis resulted in ZINC04880153 showing the lowest binding energy (?9.1 kcal/mol) with the drug target. The molecular dynamics study of the complex HisI-ZINC04880153 was conducted to analyze the stability and fluctuation of ligand within the binding pocket of HisI. The identified ligand could be analyzed in the wet-lab based experiments for future drug discovery.     

Designing allosteric modulators for active conformational state of m-glutamate G-protein coupled receptors

G-protein coupled receptors (GPCRs) are found to be attractive drug targets for the treatment of various neuronal diseases. Allosteric modulators have their role in enhancing or suppressing the effect of glutamate on mGluRs. Structure of mGluR1 was generated with the help of Modeller software by considering human B2-adrenergic GPCR protein as template. Structure of various already known drug molecules were used for similarity search in the ZINC database and a large number of similar molecules were obtained, than filtering of these molecules were done by applying drug features. Molecules were screened by Molegro Virtual Docking program and numbers of novel molecules were generated by using LigBuilder software. Finally 16 novel drug candidates were selected, which were showing better results than the seed molecule and previously known modulators. These results will help in designing and synthesis of better drugs against diseases like Epilepsy and Parkinson's.     

Identifying potential entry inhibitors for emerging Nipah virus by molecular docking and chemical-protein interaction network

Abstract

Nipah Virus (NiV) is a newly emergent paramyxovirus that has caused various outbreaks in Asian countries. Despite its acute pathogenicity and lack of approved therapeutics for human use, there is an urgent need to determine inhibitors against NiV. Hence, this work includes prospection of potential entry inhibitors by implementing an integrative structure- and network-based drug discovery approach. FDA-approved drugs were screened against attachment glycoprotein (NiV-G, PDB: 2VSM), one of the prime targets to inhibit viral entry, using a molecular docking approach that was benchmarked both on CCDC/ASTEX and known NIV-G inhibitor set. The predicted small molecules were prioritized on the basis of topological analysis of the chemical-protein interaction network, which was inferred by integrating the drug-target network, NiV-human interaction network, and human protein-protein interaction network. A total of 17 drugs were predicted to be NiV-G inhibitors using molecular docking studies that were further prioritized to 3 novel leads???Nilotinib, Deslanoside and Acetyldigitoxin???on the basis of topological analysis of inferred chemical-protein interaction network. While Deslanoside and Acetyldigitoxin belong to an already known class of anti-NiV inhibitors, Nilotinib belongs to Benzenoids chemical class that has not been reported hitherto for developing anti-NiV inhibitors. These identified drugs are expected to be successful in further experimental evaluation and therefore could be used for anti-Nipah drug discovery. Apart, we also obtained various insights into the underlying chemical-protein interaction network, based on which several important network nodes were predicted. The applicability of our proposed approach was also demonstrated by prospecting for anti-NiV phytochemicals on an independent dataset.

Communicated by Ramaswamy H. Sarma     

Potential of butein,a tetrahydroxychalcone to obliterate cancer

BackgroundDespite the major advances made in the field of cancer biology, it still remains one of the most fatal diseases in the world. It is now well established that natural products are safe and efficacious and have high potential in the prevention and treatment of different diseases including cancer. Butein is one such compound which is now found to have anti-cancer properties against various malignancies.PurposeTo thoroughly review the literature available on the anti-cancer properties of butein against different cancers and its molecular targets.MethodsA thorough literature search has been done in PubMed for butein, its biological activities especially cancer and its molecular targets.ResultsOur search retrieved several reports on the various biological activities of butein in which around 43 articles reported that butein shows potential anti-proliferative effect against a wide range of neoplasms and the molecular target varies with cancer types. Most often it targets NF-κB and its downstream pathways. In addition, butein induces the expression of genes which mediate the cell death and apoptosis in cancer cells. It also inhibits tumor angiogenesis, invasion and metastasis in prostate, liver and bladder cancers through the inhibition of MMPs, VEGF etc. Moreover, it inhibits the overexpression of several proteins and enzymes such as STAT3, ERK, CXCR4, COX-2, Akt, EGFR, Ras etc. involved in tumorigenesis.ConclusionCollectively, all these findings suggest the enormous potential and efficacy of butein as a multitargeted chemotherapeutic, chemopreventive and chemosensitizing agent against a wide range of cancers with minimal or no adverse side effects.     

Characterization of differences in substrate specificity among CYP1A1, CYP1A2 and CYP1B1: an integrated approach employing molecular docking and molecular dynamics simulations

Recent trends in new drug discovery of anticancer drugs have made oncologists more aware of the fact that the new drug discovery must target the developing mechanism of tumorigenesis to improve the therapeutic efficacy of antineoplastic drugs. The drugs designed are expected to have high affinity towards the novel targets selectively. Current research highlights overexpression of CYP450s, particularly cytochrome P450 1A1 (CYP1A1), in tumour cells, representing a novel target for anticancer therapy. However, the CYP1 family is identified as posing significant problems in selectivity of anticancer molecules towards CYP1A1. Three members have been identified in the human CYP1 family: CYP1A1, CYP1A2 and CYP1B1. Although sequences of the three isoform have high sequence identity, they have distinct substrate specificities. The understanding of macromolecular features that govern substrate specificity is required to understand the interplay between the protein function and dynamics, design novel antitumour compounds that could be specifically metabolized by only CYP1A1 to mediate their antitumour activity and elucidate the reasons for differences in substrate specificity profile among the three proteins. In the present study, we employed a combination of computational methodologies: molecular docking and molecular dynamics simulations. We utilized eight substrates for elucidating the difference in substrate specificity of the three isoforms. Lastly, we conclude that the substrate specificity of a particular substrate depends upon the type of the active site residues, the dynamic motions in the protein structure upon ligand binding and the physico‐chemical characteristics of a particular ligand. Copyright © 2016 John Wiley & Sons, Ltd.     

Characterization and molecular basis of the oligomeric structure of HIV-1 nef protein

The Nef protein of human immunodeficiency virus type I (HIV-1) is an important determinant for the onset of AIDS disease. The self-association properties of HIV-1 Nef are analyzed by chemical cross-linking, dynamic light scattering, equilibrium analytical ultracentrifugation, and NMR spectroscopy. The experimental data show that the HIV-1 Nef core domain forms stable homo-dimers and trimers in solution, but not higher oligomers. These Nef homomers are not covalently linked by disulfide bridges, and the equilibrium between these forms is dependent on the Nef concentration. We further provide the molecular basis for the Nef core dimers and trimers obtained by analysis of crystallographic models. Oligomerization of biological polypeptides is a common tool used to trigger events in cellular signaling and endocytosis, both of which are targeted by Nef. The quaternary structure of Nef may be of physiological importance and may help to connect its cellular targets or to increase affinity of the viral molecule for its ligands. The herein described models for Nef dimers and trimers will allow further mutational studies to elucidate their role in vivo. These results provide novel insight into the structural and functional relationships of this important viral protein. Moreover, the oligomer interface may represent a novel target for the design of antiviral agents.     

Finding off‐targets,biological pathways,and target diseases for chymase inhibitors via structure‐based systems biology approach

Off‐target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off‐targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off‐target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off‐targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off‐targets into biological pathways and to establish links between pathways and particular adverse effects. Off‐targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off‐targets. These off‐targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors. Proteins 2015; 83:1209–1224. © 2014 Wiley Periodicals, Inc.     

Coumarin hybrids as novel therapeutic agents

Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, anti-inflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimer’s disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure–activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders.     

Potential targets of severe acute respiratory syndrome coronavirus 2 of clinical drug fluvoxamine: Docking and molecular dynamics studies to elucidate viral action

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued evolving for survival and adaptation by mutating itself into different variants of concern, including omicron. Several studies and clinical trials found fluvoxamine, an Food and Drug Administration-approved antidepressant drug, to be effective at preventing mild coronavirus disease 2019 (COVID-19) from progressing to severe diseases. However, the mechanism of fluvoxamine's direct antiviral action against COVID-19 is still unknown. Fluvoxamine was docked with 11 SARS-CoV-2 targets and subjected to stability, conformational changes, and binding free energy analyses to explore its mode of action. Of the targets, nonstructural protein 14 (NSP14), main protease (Mpro), and papain-like protease (PLpro) had the best docking scores with fluvoxamine. Consistent with the docking results, it was confirmed by molecular dynamics simulations that the NSP14 N7-MTase ((N7-guanine)-methyltransferase)–fluvoxamine, Mpro–fluvoxamine, and PLpro–fluvoxamine complexes are stable, with the lowest binding free energies of −105.1, −82.7, and − 38.5 kJ/mol, respectively. A number of hotspot residues involved in the interaction were also identified. These include Glu166, Asp187, His41, and Cys145 in Mpro, Gly163 and Arg166 in PLpro, and Glu302, Gly333, and Phe426 in NSP14, which could aid in the development of better antivirals against SARS-CoV-2.     

Recent patents involving virus nucleotide sequences; host defense, RNA silencing and expression vector strategies

Improved knowledge of the molecular biology of viruses, including recent gains in virus sequence data analysis, has greatly contributed to recent innovations in medical diagnostics, therapeutics, drug development and other related areas. Virus sequences have been used for the development of vaccines and antiviral agents to block the spread of viral infections, as well as to target and battle chronic diseases such as cancer. Virus sequences are now routinely employed in a wide array of RNA silencing technologies. Viruses can also be engineered into expression vectors which in turn can be used as protein production platforms as well as delivery vehicles for gene therapies. This review article outlines a number of patents that have been recently issued with respect to virus sequence data and describes some of their biotechnological applications.     

Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2

A series of thiuram disulfides 1–6 which had been previously synthesized and characterized,^[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.     

An integrated in silico approach to understand protein–protein interactions: human meprin-β with fetuin-A

Abstract

Human meprin-β, a zinc metalloprotease belonging to the astacin family, have been found to be associated with many pathological conditions like inflammatory bowel disease, fibrosis and neurodegenerative disease. The inhibition of meprin-β by various inhibitors, both macromolecular and small molecules, is crucial in the control of several diseases. Human fetuin-A, a negative acute phase protein involved in inflammatory disease, has recently been identified as an endogenous inhibitor for meprin-β. In this computational study, an integrated in silico approach was performed using existing structural information of meprin-β coupled with ab initio modelling of human fetuin-A to predict a rational model of the complex through protein–protein docking. Further, the models were optimized and validated to generate an ensemble of conformations through extensive molecular dynamics simulation. Virtual alanine scanning mutagenesis was explored to identify hotspot residues on both proteins significant for protein–protein interaction (PPI). The results of the study provide structural insight into PPI between meprin-β and fetuin-A which can be useful in designing molecules to modulate meprin-β activity.

Communicated by Ramaswamy H. Sarma     

New potential inhibitors of mTOR: a computational investigation integrating molecular docking,virtual screening and molecular dynamics simulation

The mTOR (mammalian or mechanistic Target Of Rapamycin), a complex metabolic pathway that involves multiple steps and regulators, is a major human metabolic pathway responsible for cell growth control in response to multiple factors and that is dysregulated in various types of cancer. The classical inhibition of the mTOR pathway is performed by rapamycin and its analogs (rapalogs). Considering that rapamycin binds to an allosteric site and performs a crucial role in the inhibition of the mTOR complex without causing the deleterious side effects common to ATP-competitive inhibitors, we employ ligand-based drug design strategies, such as virtual screening methodology, computational determination of ADME/Tox properties of selected molecules, and molecular dynamics in order to select molecules with the potential to become non-ATP-competitive inhibitors of the mTOR enzymatic complex. Our findings suggest five novel potential mTOR inhibitors, with similar or better properties than the classic inhibitor complex, rapamycin.     

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

Theranostics cover emerging technologies for cell biomarking for disease diagnosis and targeted introduction of drug ingredients to specific malignant sites. Theranostics development has become a significant biomedical research endeavor for effective diagnosis and treatment of diseases, especially cancer. An efficient biomarking and targeted delivery strategy for theranostic applications requires effective molecular coupling of binding ligands with high affinities to specific receptors on the cancer cell surface. Bioaffinity offers a unique mechanism to bind specific target and receptor molecules from a range of non‐targets. The binding efficacy depends on the specificity of the affinity ligand toward the target molecule even at low concentrations. Aptamers are fragments of genetic materials, peptides, or oligonucleotides which possess enhanced specificity in targeting desired cell surface receptor molecules. Aptamer–target binding results from several inter‐molecular interactions including hydrogen bond formation, aromatic stacking of flat moieties, hydrophobic interaction, electrostatic, and van der Waals interactions. Advancements in Systematic Evolution of Ligands by Exponential Enrichment (SELEX) assay has created the opportunity to artificially generate aptamers that specifically bind to desired cancer and tumor surface receptors with high affinities. This article discusses the potential application of molecular dynamics (MD) simulation to advance aptamer‐mediated receptor targeting in targeted cancer therapy. MD simulation offers real‐time analysis of the molecular drivers of the aptamer‐receptor binding and generate optimal receptor binding conditions for theranostic applications. The article also provides an overview of different cancer types with focus on receptor biomarking and targeted treatment approaches, conventional molecular probes, and aptamers that have been explored for cancer cells targeting.     

Target network analysis of adiponectin,a multifaceted adipokine

Application of network analysis to dissect the potential molecular mechanisms of biological processes and complicated diseases has been the new trend in biology and medicine in recent years. Among which, the protein–protein interactions (PPI) networks attract interests of most researchers. Adiponectin, a cytokine secreted from adipose tissue, participates in a number of metabolic processes, including glucose regulation and fatty acid metabolism and involves in a series of complicated diseases from head to toe. Hundreds of proteins including many identified and potential drug targets have been reported to be involved in adiponectin related signaling pathways, which comprised a complicated regulation network. Therapeutic target database (TTD) provides extensive information about the known and explored therapeutic protein targets and the signaling pathway information. In this study, adiponectin associated drug targets based PPI was constructed and its topological properties were analyzed, which might provide some insight into the dissection of adiponectin action mechanisms and promote adiponectin signaling based drug target identification and drug discovery. J. Cell. Biochem. 114: 1145–1152, 2013. © 2012 Wiley Periodicals, Inc.     

Design,synthesis and biological evaluation of small molecular polyphenols as entry inhibitors against H5N1

To find novel compounds against H₅N₁, three series of known or novel small molecular polyphenols were synthesized and tested in vitro for anti-H₅N₁ activity. In addition, the preliminary structure–antiviral activity relationships were elaborated. The results showed that some small molecular polyphenols had better anti-H₅N₁ activity, and could serve as novel virus entry inhibitors against H₅N₁, likely targeting to HA2 protein. Noticeably, compound 4a showed the strongest activity against H₅N₁ among these compounds, and the molecular modeling analysis also suggested that this compound might target to HA2 protein. Therefore, compound 4a is well qualified to serve as a lead compound or scaffold for the further development of H₅N₁ entry inhibitor.     

The therapeutic potential of antisense oligonucleotides

Specific inhibition of gene expression by antisense agents provides the basis for rational drug discovery based on molecular targets. Due to the specificity of Watson-Crick base-pair hybridization, antisense oligodeoxynucleotides have been used extensively in attempts to inhibit gene expression in both in vitro and in vivo models. Analogues modified from normal phosphodiester oligodeoxynucleotides have entered clinical trials against diseases including AIDS and cancer. Although the precise mechanism of action of these drugs has not been clarified, these oligodeoxynucleotides offer considerable promise as novel molecular therapeutics. We review the recent attempts to harness the therapeutic potential of these oligodeoxynucleotides and appraise the near-term prospects for antisense technology.