Molecular Simulations Group

Panaji, India

Molecular Simulations Group

Panaji, India
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Pissurlenkar R.R.S.,Molecular Simulations Group
RSC Advances | Year: 2015

Antimicrobial peptides (AMPs) are naturally occurring small peptides which are an innate part of the host's defense mechanism. They are active against both Gram-negative and Gram-positive bacteria, various viruses, fungi, and parasites. There is little consensus in the amino acid sequences of AMPs but evidently they do possess some definite common features, such as relative hydrophobic and a positively charged amphipathic structure that has been associated with the biological activity. Optimization of the activity and specificity of the AMPs using large peptide libraries is a tedious and expensive route. In this venture, QSAR can be used to shed light or reveal the structural features that should be incorporated in the design of new AMPs. However within the realm of QSAR, 3D-QSAR of peptides is an overwhelming task due to the sheer number of conformational degrees of freedom for peptides. To achieve this, we propose the use of a validated 2D-QSAR technique coined HomoSAR that is specifically designed for peptide QSAR. It has the ability to extract all necessary information from a set of peptides to elucidate the underlying structure activity relationships, based on homology principles and similarity techniques. The present work is a comprehensive study on a dataset of protegrin antimicrobial peptides isolated from porcine leukocytes with a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, as well as the fungus C. albicans and HIV-1 virus. The HomoSAR models for antimicrobial activity against six different species highlighted two major determinants of activity; firstly the optimal length of protegrins for exhibiting broad-spectrum antimicrobial activity against bacteria and fungi is 16 residues. Secondly, for antimicrobial activity against the yeast C. albicans, it turns out that it is the electronic property that should be tempered to modulate activity. This is not a major attribute for both Gram negative and Gram positive bacteria. © The Royal Society of Chemistry.

Bhatachrya D.,Molecular Simulations Group
International Journal of Pharma and Bio Sciences | Year: 2015

The polyphenol rich extracts of leaves of P. guajava were evaluated for chemoprofiling and HPLC with respect to standard quercetin. With the HPLC it was calculated that 0.02% quercetin was present in total extracts. After that the complexation with phospholipids was carried out to convert the polyphenols of extracts of leaves of P.guajava into their bio-absorbable lipophilic fraction which improve their pharmacokinetic profile. The activities were evaluated by lipid peroxidation inhibitory activity and anti-inflammatory activity using various in-vitro and in-vivo model. The superiority of the action of complexes has demonstrated the concepts behind the product development of the herbal raw material. In sum the synergism of the bio activity profile of phyto-constituents is possible by their complexation with phospholipids.

Pissurlenkar R.R.S.,Molecular Simulations Group | Coutinho E.C.,Molecular Simulations Group | Katare O.P.,Panjab University | Chandra R.,University of Delhi
Carbohydrate Polymers | Year: 2014

Telmisartan (TEL) requires superior bioavailability in cancer cell compartments. To meet these challenges, we have synthesized a 2-HP-β-CD-TEL complex with stability constant (Kc) of 2.39 × 10-3 mM. The absence in the FTIR spectrum of 2-HP-β-CD-TEL complex of the characteristic peaks of TEL at 1699 cm-1 (carboxylic acid) and 741 and 756 cm-1 (1,2-disubstituted benzene ring vibrations), is indicative of the encapsulation of TEL in the 2-HP-β-CD cavity. DSC and PXRD also confirmed the synthesis and amorphous structure of complex. The interaction of TEL with 2-HP-β-CD was examined by NMR and 2D-ROESY which affirms the encapsulation of TEL in the 2-HP-β-CD cavity in at least two orientations with equal binding energies. The complex also exhibited its superiority in both in vitro release and cytotoxicity experiments on prostate cancer, PC-3 cells as compared to free drug. These data warrant an in depth in vivo to scale-up the technology for the management of prostate cancer.© 2013 Elsevier Ltd. All rights reserved.

Borana M.S.,University of Mumbai | Mishra P.,Tata Institute of Fundamental Research | Pissurlenkar R.R.S.,Molecular Simulations Group | Hosur R.V.,University of Mumbai | And 2 more authors.
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2014

Interaction of small molecule inhibitors with protein aggregates has been studied extensively, but how these inhibitors modulate aggregation kinetic parameters is little understood. In this work, we investigated the ability of two potential aggregation inhibiting drugs, curcumin and kaempferol, to control the kinetic parameters of aggregation reaction. Using thioflavin T fluorescence and static light scattering, the kinetic parameters such as amplitude, elongation rate constant and lag time of guanidine hydrochloride-induced aggregation reactions of hen egg white lysozyme were studied. We observed a contrasting effect of inhibitors on the kinetic parameters when aggregation reactions were measured by these two probes. The interactions of these inhibitors with hen egg white lysozyme were investigated using fluorescence quench titration method and molecular dynamics simulations coupled with binding free energy calculations. We conclude that both the inhibitors prolong nucleation of amyloid aggregation through binding to region of the protein which is known to form the core of the protein fibril, but once the nucleus is formed the rate of elongation is not affected by the inhibitors. This work would provide insight into the mechanism of aggregation inhibition by these potential drug molecules. © 2014 Elsevier B.V.

Ugarkar A.G.,Molecular Simulations Group | Ambre P.K.,Molecular Simulations Group | Coutinho E.C.,Molecular Simulations Group | Nandan S.,Chemworx | Pissurlenkar R.R.S.,Molecular Simulations Group
Canadian Journal of Chemistry | Year: 2014

GPR119 is a potential target for the treatment of diabetes mellitus. GPR119 agonists minimize the side-effects observed with sulphonyl ureas and glucagon-like peptide 1 analogs. Various reported GPR119 agonists from various patents were selected for the study and a 2D-QSAR study (HQSAR) was carried out. Fifty-five molecules were selected for the study. The study was performed on a training set of 40 structurally diverse molecules with reported biological activity. The most significant HQSAR model (q2 = 0.87, r2 = 0.99) was obtained using atoms, bond, connection, and acceptor and donor as fragment distinction. The fragment size was kept at 4-7. The predictive ability of the model was evaluated by an external test set containing 15 molecules not included in the training set, and the predicted values were in good agreement with the experimental values. The important fragments determined by the study were used to design new drug candidates having increased biological activity and comparable physicochemical properties. © 2014 Published by NRC Research Press.

Muthu S.A.,University of Mumbai | Mothi N.,University of Mumbai | Shiriskar S.M.,University of Mumbai | Pissurlenkar R.R.S.,Molecular Simulations Group | And 2 more authors.
Archives of Biochemistry and Biophysics | Year: 2016

Aggregation of globular proteins is an intractable problem which generally originates from partially folded structures. The partially folded structures first collapse non-specifically and then reorganize into amyloid-like fibrils via one or more oligomeric intermediates. The fibrils and their on/off pathway intermediates may be toxic to cells and form toxic deposits in different human organs. To understand the basis of origins of the aggregation diseases, it is vital to study in details the conformational properties of the amyloidogenic partially folded structures of the protein. In this work, we examined the effects of ofloxacin, a synthetic fluoroquinolone compound on the fibrillar aggregation of hen egg-white lysozyme. Using two aggregation conditions (4M GuHCl at pH 7.0 and 37 °C; and pH 1.7 at 65 °C) and a number of biophysical techniques, we illustrate that ofloxacin accelerates fibril formation of lysozyme by binding to partially folded structures and modulating their secondary, tertiary structures and surface hydrophobicity. We also demonstrate that Ofloxacin-induced fibrils show polymorphism of morphology, tinctorial properties and hydrophobic surface exposure. This study will assist in understanding the determinant of fibril formation and it also indicates that caution should be exercised in the use of ofloxacin in patients susceptible to various aggregation diseases. © 2016 Elsevier Inc. All rights reserved.

Ambre P.K.,Molecular Simulations Group | Pissurlenkar R.R.S.,Molecular Simulations Group | Coutinho E.C.,Molecular Simulations Group | Iyer R.P.,Spring Bank Pharmaceuticals
Canadian Journal of Chemistry | Year: 2012

Inhibition of checkpoint kinase-1 (Chk1) by small molecules is of great therapeutic interest in the field of oncology and for understanding cell-cycle regulations. This paper presents a model with elements from docking, pharmacophore mapping, the 3D-QSAR approaches CoMFA, CoMSIA and CoRIA, and virtual screening to identify novel hits against Chk1. Docking, 3D-QSAR (CoRIA, CoMFA and CoMSIA), and pharmacophore studies delineate crucial site points on the Chk1 inhibitors, which can be modified to improve activity. The docking analysis showed residues in the proximity of the ligands that are involved in ligand-receptor interactions, whereas CoRIA models were able to derive the magnitude of these interactions that impact the activity. The ligand-based 3D-QSAR methods (CoMFA and CoMSIA) highlight key areas on the molecules that are beneficial and (or) detrimental for activity. The docking studies and 3D-QSAR models are in excellent agreement in terms of binding-site interactions. The pharmacophore hypotheses validated using sensitivity, selectivity, and specificity parameters is a four-point model, characterized by a hydrogen-bond acceptor (A), hydrogen-bond donor (D), and two hydrophobes (H). This map was used to screen a database of 2.7 million druglike compounds, which were pruned to a small set of potential inhibitors by CoRIA, CoMFA, and CoMSIA models with predicted activity in the range of 8.5-10.5 log units. © 2012 Published by NRC Research Press.

Pandey A.D.,University of Mumbai | Mohammed H.,University of Mumbai | Pissurlenkar R.R.S.,Molecular Simulations Group | Karnik A.V.,University of Mumbai
ChemPlusChem | Year: 2015

(S)-(-)-2-(α-Hydroxyethyl)benzimidazole (1)-derived diastereomeric monoaza-[18]crown-6 compounds 5 and 6 were synthesised with an additional chiral centre bearing a phenyl ring. The aim was to achieve enhanced enantioselective discrimination, compared with monoaza-[15]crown-5 (7). Surprisingly, reversal of enantioselective binding for chiral guest enantiomers between the two differently sized [15]crown-5 and [18]crown-6 azacrowns were discovered; all three were prepared from the same parent compound, 1. To complete the observations, another [18]crown-6-sized azacrown (10) without an additional chiral centre was synthesised from 1 and screened for its enantioselective binding abilities towards the chiral guest enantiomers investigated; these results corroborated the observations. Single-crystal XRD analysis and molecular docking studies revealed that changes to the conformational aspects of [18]crown-6 and [15]crown-5 azacrowns were the major contributing factors to this peculiar behaviour. Switching sides: The size of a chiral azacrown rather than the configuration of the chiral center/s in the hosts is the dominant influence on the enantioselective binding of guests. Thus, S-(-)-2(α-hydroxyethyl)benzimidazole-derived [15]crown-5 azacrown exhibit a preference for the S enantiomer of amino guests, whereas S-(-)-2(α-hydroxyethyl)benzimidazole-derived [18]crown-6 azacrowns exhibit a preference for the R enantiomer (see scheme). Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pandey A.D.,University of Mumbai | Pissurlenkar R.R.S.,Molecular Simulations Group | Karnik A.V.,University of Mumbai
Journal of Inclusion Phenomena and Macrocyclic Chemistry | Year: 2015

Benzimidazoles derived from lactic acid and mandelic acid were employed as photosignaling synthons to construct 15-C-5 azacrowns 3 & 4 with difference in electronic environments at the carbon attached to 2-position. These receptors were used as probes for cation sensing using UV-Vis and fluorescence titration techniques. Although both the receptors have identical macrocyclic backbone and are found selective for Cu2+, receptor 3 displayed stronger binding towards Cu2+ in comparison to 4. The addition of Cu2+ to the probes 3 & 4 in solution caused quenching of fluorescence. The results clearly indicate that the stability of Cu2+ complexes of 3 and 4 depends on different factors. The association constant, KSV for 3 with Cu2+ was (1.53 9 105 M-1) an order higher than that exhibited by 4 for Cu2+ (9.27 9 104 M-1). © Springer Science+Business Media Dordrecht 2014.

Ratnaparkhi A.,University of Mumbai | Muthu S.A.,University of Mumbai | Shiriskar S.M.,University of Mumbai | Pissurlenkar R.R.S.,Molecular Simulations Group | And 2 more authors.
Journal of Biomolecular Structure and Dynamics | Year: 2015

Hesperidin (HESP), a flavanone glycoside, shows high antioxidant properties and posses ability to go through the blood-brain barrier. Therefore, it could be a potential drug molecule against aggregation based diseases such as Alzheimers, Parkinsons, and systemic amyloidoses. In this work, we investigated the potential of HESP to interact with hen egg-white lysozyme (HEWL) monomer and prevent its aggregation. The HESP-HEWL binding studies were performed using a fluorescence quenching technique, molecular docking and molecular dynamics simulations. We found a strong interaction of HESP with the lysozyme monomer (Ka, ∼ 5 × 104 M-1) mainly through hydrogen bonding, water bridges, and hydrophobic interactions. We showed that HESP molecule spanned the highly aggregation prone region (amino acid residues 48-101) of HEWL and prevented its fibrillar aggregation. Further, we found that HESP binding completely inhibited amorphous aggregation of the protein induced by disulfide-reducing agent tries-(2-carboxyethyl) phosphine. Conformational and stability studies as followed by various tertiary and secondary structure probes revealed that HESP binding only marginally affected the lysozyme monomer conformation and increased both stability and reversibility of the protein against thermal denaturation. Future studies should investigate detail effects of HESP on solvent dynamics, structure, and toxicity of various aggregates. The answers to these questions will not only target the basic sciences, but also have application in biomedical and biotechnological sciences. © 2014 Taylor & Francis.

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