In Silico Research Laboratory

Indore, India

In Silico Research Laboratory

Indore, India
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Bandaru S.,Osmania University | Hema Prasad M.,Osmania University | Jyothy A.,Osmania University | Nayarisseri A.,In silico Research Laboratory | Yadav M.,Softvision College
Current Topics in Medicinal Chemistry | Year: 2013

β2 agonists and anticholinergics are two major classes of bronchodilators which form first line of drugs recommended in symptomatic treatment of asthma and COPD. Combinational therapy involving β agonists and anticholinergics prove more effective in treating airway disease than use of either agent alone. In present investigation, binding modes of Muscarinic Antagonism and β 2 Agonism (MABA) conjugates designed by Lyn et al. were revealed on structural grounds adopting molecular docking techniques. The conjugates tether β 2 motif onto M3 motif which makes it a single molecule that acts as both β 2 agonist and antimuscarinic agent. Series of conjugates were docked against β 2 adrenergic receptor and modeled M3 muscarinic acetylcholine receptor and pharmacophoric features were identified. Upon screening the conjugates on the basis of receptor ligand free energy, hydrogen bonding and internal electrostatic interaction, conjugate 11 demonstrated superior interactions with the receptors compared to remaining conjugates in the series. While, in vitro results and in silico outcomes are in agreement to reveal that conjugate 11 to possess best pharmacological profile, binding modes obtained in docking can be utilized to design new conjugates with improved biological activity. A close study of receptor residues in binding site and atoms, groups and substructures of conjugates may be used to develop favourable secondary valence forces towards receptor-ligand interactions. © 2013 Bentham Science Publishers.


Phanse N.,PMB Gujarati Science College | Rathore P.,Institute of Management Sciences | Patel B.,P.A. College | Nayarisseri A.,In Silico Research Laboratory
Journal of Pharmacy Research | Year: 2013

Aim: The phenotypic and phylogenetic characterization of an alkalophilic bacterium producing two industrially important enzymes - alkaline protease and alkaline amylase, was performed. A Gram-positive, rod-shaped, spore-forming alkalophilic bacterium (2b) isolated from alkaline dairy soil of Indore region of Madhya Pradesh, was selected in this work. Methods: The alkalophile was subjected to a taxonomic investigation, including standard bacteriological characterization and 16S rRNA gene sequencing. Phylogenetic trees were constructed by different treeing algorithms: neighbour joining, maximum parsimony tree, maximum-likelihood and UPGMA method using MEGA5 software. The secondary structures of 16S rRNA gene sequence were predicted using GeneBee package and UNAFOLD, a Linux based software. Results: Its overall biochemical, physiological and phylogenetic characteristics indicated that strain 2b is an alkaliphilic Bacillus belonging to the species agaradhaerens. The free energy of the secondary structure of rRNA was -171.7 and -265.13 kcal/mol respectively. The structure obtained with a Gibb's free energy, δ. G -265.13 kcal/mol by UNAFOLD seems to be more stable in the present study. Conclusion: The taxonomic investigation identifies 2b as Bacillus agaradhaerens. © 2013 JPR Solutions.


Bandaru S.,Osmania University | Bandaru S.,National Institute of Pharmaceutical Education and Research | Alvala M.,National Institute of Pharmaceutical Education and Research | Akka J.,Osmania University | And 5 more authors.
Current Pharmaceutical Design | Year: 2016

Background: A subset of asthmatics shows refractoriness to Salbutamol owing to ADRB2 gene C → T polymorphism (rs 1800888) that substitutes Thr to Ile at the position 164 in the β2 adrenergic receptor leading to sub-optimal binding of Salbutamol. The present study aims to associate the Salbutamol (200 mcg) refractoriness with the polymorphism and select the best existing agonist with optimal binding affinity against wild and mutated receptor and further identify high affinity compound, irrespectively targeting wild and mutated receptor through virtual screening methods. Methods: Responders to Salbutamol were categorized, if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility less than 12% were non-responders. The genotyping for polymorphism was performed by ARMS PCR method. Established agonists with consistent binding affinity against wild and mutated receptors formed query compound to identify high affinity molecule from Phase database through 7 point pharmacophore based screening. Results: Polymorphism was significantly associated with non-responders (p= < 0.05) demonstrating it as a major factor of Salbutamol refractoriness. Results from Glide Docking showed that Fenoterol had highest affinity for mutated receptor and stood as second best (after Salbutamol) high affinity agonist for wild receptor among the established β2 agonists. Therefore Fenoterol formed a query molecule (7 point pharmacophore) in identification of high affinity compound for virtual screening process. Conclusion: Compound CACPD2011a-0001278239 identified through virtual screening against 4 million compounds in phase database was shown to irrespectively target both wild and mutated β2 adrenergic receptor with high and consistent affinity which was par greater than established β2agonists. © 2016 Bentham Science Publishers.


PubMed | P.A. College, In silico Research Laboratory, Osmania University and Devi Ahilya University
Type: Journal Article | Journal: Bioinformation | Year: 2015

Psoriasis is one of the most prevalent chronic inflammatory diseases of the skin. The Wnt pathways have been documented to play essential role in stem cell self-renewal and keratinocyte differentiation in the skin. Antagonizing the Wnt5a protein would emerge as a novel therapeutics in psoriasis treatment. In this view, we have developed and characterized series of compounds by attaching varied tertiary alkyloxy carbonyl groups at the N-terminal end of the hexapeptide (Met-Asp-Gly-Cys-Glu-Leu) bestowed to inhibit Wnt/Ca2+ signaling in psoriasis. Hexapeptide compound with 1,1-diphenylethoxy carbonyl group attached to N-terminal end of hexapeptide demonstrated highest binding affinity amongst all the evaluated compounds. The compound identified in the study can be subjected further for in vitro and in vivo studies for ADMET properties.


PubMed | National Institute of Pharmaceutical Education and Research, In silico Research Laboratory, Government General and Chest Hospital and Osmania University
Type: Journal Article | Journal: Bioinformation | Year: 2015

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs.mTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506-binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC-alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases.


PubMed | National Institute of Pharmaceutical Education and Research, In silico Research Laboratory, Government General and Chest Hospital and Osmania University
Type: Journal Article | Journal: Gene | Year: 2016

Thr164Ile polymorphism in the ADRB2 gene encoding 2 adrenergic receptor (2AR) has its functional consequence in declining ligand-receptor interactions and depressed coupling of 2AR to adenylcyclase. In the present study, we sought to evaluate the possible association of Thr164Ile polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol and varying degrees of severity.Three hundred and ninety eight clinically diagnosed patients and four hundred and fifty six healthy controls were enrolled in the study. Patients were classified into severity classes according to the Global Initiative for Asthma (GINA) guidelines. To assess bronchodilator response, spirometry was performed before and 15min after Salbutamol (200g) delivery. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility <12% were classified as non-responders. Further, responding phenotypes were stratified into severity groups. Genotyping was carried out by ARMS-PCR technique. Statistical methods were applied to test the significance of the results.In the present study, polymorphism was not associated with disease susceptibility however; there was significant association with non-responding asthmatics. In case of severity subsets, the polymorphism was not associated with milder subtypes; although, notable association was observed with moderate and severe asthma subtypes. In addition, the polymorphism was significantly associated with non-responding patients with severe asthma.In south Indian population, the ADRB2 Thr164Ile polymorphism may not form susceptible variant to develop asthma, however, it can form a predictive maker for bronchodilator (Salbutamol) response in severe asthmatics.


PubMed | National Institute of Pharmaceutical Education and Research, Central University of Punjab, In silico Research Laboratory, Jawaharlal Nehru Technological University and Osmania University
Type: Journal Article | Journal: Bioinformation | Year: 2015

Phenytoin (PHT) and Carbamazepine (CBZ) are excellent sodium channel blockers administered in clinical treatment of epileptic seizures. However, the narrow therapeutic range and limited pharmacokinetics of these drugs have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule with superior pharmacological profile than PHT and CBZ through In silico approaches. PHT and CBZ served as query small molecules for Tanimoto based similarity search with a threshold of 95% against PubChem database. Aided by MolDock algorithm, high affinity similar compound against each query was retrieved. PHT and CBZ and their respective similar were further tested for toxicity profiles, LC 50 values and biological activity. Compounds, NSC403438 and AGN-PC-0BPCBP respectively similar to PHT and CBZ demonstrated higher affinity to sodium channel protein than their respective leads. Of particular relevance, NSC403438 demonstrated highest binding affinity bestowed with least toxicity, better LC 50 values and optimal bioactivity. NSC403438 was further mapped for its structure based pharmacophoric features. In the study, we report NSC403438 as potential sodium channel blocker as a better candidate than PHT and CBZ which can be put forth for pharmacodynamic and pharmacokinetic studies.AEDs - Antiepileptic drugs, BLAST - Basic Local Alignment Search Tool, CBZ - Carbamazepine, GEFS+ - Generalized Epilepsy with Febrile Seizures Plus, GPCR - G Protein Coupled Receptor, Nav - Sodium channel with specific voltage conduction, PDB - Protein Data Bank, PHT - Phenytoin, PIR - Protein Information resources, SAVES - Structural Analysis and Verification Server, VGSC - Voltage-gated Sodium channels.


Sinha C.,University of Lucknow | Nischal A.,University of Lucknow | Bandaru S.,Osmania University | Kasera P.,In silico Research Laboratory | And 3 more authors.
Current Topics in Medicinal Chemistry | Year: 2015

available antiviral drugs target the pol-encoded retroviral enzymes or integrases, in addition, inhibitors that target HIV-1 envelope-receptor interactions have also been recently approved. Recent understanding of the interactions between HIV-1 and host restriction factors has provided fresh avenues for development of novel antiviral drugs. For example, viral infectivity factor (Vif) now surfaced as an important therapeutic target in treatment of HIV infection. Vif suppresses A3G antiviral activity by targeting these proteins for polyubiquitination and proteasomal degradation. In the present study we analyzed the inhibitory potential of VEC5 and RN18 to inhibit the Vif-A3G interaction through protein- protein docking studies. Perusal of the study showed that, VEC5 and RN18 though inhibits the interaction however showed sub optimal potential. To overcome this set back, we identified 35 structural analogues of VEC5 and 18 analogues of RN18 through virtual screening approach. Analogue with PubCID 71624757 and 55358204 (AKOS006479723) -structurally akin to VEC5 and RN18 respectively showed much appreciable interaction than their respective parent compound. Evident from Vif-A3G; protein - protein docking studies, analogue PubCID 71624757 demonstrated 1.08 folds better inhibitory potential than its parent compound VEC5 while analogue PubCID 55358204 was 1.15 folds better than RN18. Further these analogues passed drug likeness filters and predicted to be non- toxic. We expect these analogues can be put to pharmacodynamic studies that can pave way the breakthrough in HIV therapeutics. © 2015 Bentham Science Publishers.


PubMed | In silico Research Laboratory
Type: Journal Article | Journal: Interdisciplinary sciences, computational life sciences | Year: 2014

The PDB file format, is a text format characterizing the three dimensional structures of macro molecules available in the Protein Data Bank (PDB). Determined protein structure are found in coalition with other molecules or ions such as nucleic acids, water, ions, Drug molecules and so on, which therefore can be described in the PDB format and have been deposited in PDB database. PDB is a machine generated file, its not human readable format, to read this file we need any computational tool to understand it. The objective of our present study is to develop a free online software for retrieval, visualization and reading of annotation of a protein 3D structure which is available in PDB database. Main aim is to create PDB file in human readable format, i.e., the information in PDB file is converted in readable sentences. It displays all possible information from a PDB file including 3D structure of that file. Programming languages and scripting languages like Perl, CSS, Javascript, Ajax, and HTML have been used for the development of PDB Explorer. The PDB Explorer directly parses the PDB file, calling methods for parsed element secondary structure element, atoms, coordinates etc. PDB Explorer is freely available at http://www.pdbexplorer.eminentbio.com/home with no requirement of log-in.


PubMed | In silico Research Laboratory
Type: Journal Article | Journal: Asian Pacific journal of cancer prevention : APJCP | Year: 2016

Small molecule tyrosine kinase inhibitors targeting HER 2 receptors have emerged as an important therapeutic approach in inhibition of downstream proliferation and survival signals for the treatment of breast cancers. Recent drug discovery efforts have demonstrated that naturally occurring polyphenolic compounds like delphinidin have potential to inhibit proliferation and promote apoptosis of breast cancer cells by targeting HER2 receptors. While delphinidin may thus reduce tumour size, it is associated with serious side effects like dysphonia. Owing to the narrow therapeutic window of delphinidin, the present study aimed to identify high affinity compounds targeting HER2 with safer pharmacological profiles than delphinidin through virtual screening approaches. Delphinidin served as the query parent for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. The compounds retrieved were further subjected to Lipinski and Verbers filters to obtain drug like agents, then further filtered by diversity based screens with a cut off of 0.6. The compound with Pubchem ID: 91596862 was identified to have higher affinity than its parent. In addition it also proved to be non-toxic with a better ADMET profile and higher kinase activity. The compound identified in the study can be put to further in vitro drug testing to complement the present study.

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