Pradeep K Naik

Publications of Pradeep K Naik

• Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9-amino-α-noscapine from natural α-noscapine.

  Authors: Naresh K Manchukonda, Balasubramanian Sridhar, Pradeep K Naik, Harish C Joshi, Srinivas Kantevari

  Bioorganic & medicinal chemistry letters. 02/2012; 22(8):2983-7.

  Facile synthesis of natural α-noscapine analogue, 9-amino-α-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromaticFacile synthesis of natural α-noscapine analogue, 9-amino-α-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-noscapine (obtained by bromination of natural α-noscapine) with NaN(3) in DMSO at 130°C in the presence of l-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-α-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units.

• In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin).

  Authors: Pradeep K Naik, Manu Lopus, Ritu Aneja, Surya N Vangapandu, Harish C Joshi

  Journal of computer-aided molecular design. 12/2011; 26(2):233-47.

  Our screen for tubulin-binding small molecules that do not depolymerize bulk cellular microtubules, but based upon structural features of well known microtubule-depolymerizing colchicine andOur screen for tubulin-binding small molecules that do not depolymerize bulk cellular microtubules, but based upon structural features of well known microtubule-depolymerizing colchicine and podophyllotoxin, revealed tubulin binding anti-cancer property of noscapine (Ye et al. in Proc Natl Acad Sci USA 95:2280-2286, 1998). Guided by molecular modelling calculations and structure-activity relationships we conjugated at C9 of noscapine, a folate group-a ligand for cellular folate receptor alpha (FRα). FRα is over-expressed on some solid tumours such as ovarian epithelial cancers. Molecular docking experiments predicted that a folate conjugated noscapine (Targetin) accommodated well inside the binding cavity (docking score -11.295 kcal/mol) at the interface between α- and β-tubulin. The bulky folate moiety of Targetin is extended toward lumen of microtubules. The binding free energy (ΔG (bind)) computed based on molecular mechanics energy minimization was -221.01 kcal/mol that revealed favourable interaction of Targetin with the receptor. Chemical synthesis, tubulin-binding experiments, and anti-cancer activity in vitro corroborate fully well with the molecular modelling experiments. Targetin binds tubulin with a dissociation constant (K (d) value) of 149 ± 3.0 μM and decreases the transition frequencies between growth and shortening phases of microtubule assembly dynamics at concentrations that do not alter the total polymer mass. Cancer cells in general were more sensitive to Targetin compared with the founding compound noscapine (IC(50) in the range of 15-40 μM). Quite strikingly, ovarian cancer cells (SKOV3 and A2780), known to overexpress FRα, were much more sensitive to targetin (IC(50) in the range of 0.3-1.5 μM).

• Rational design of novel anti-microtubule agent (9-azido-noscapine) from quantitative structure activity relationship (QSAR) evaluation of noscapinoids.

  Authors: Seneha Santoshi, Pradeep K Naik, Harish C Joshi

  Journal of biomolecular screening. 10/2011; 16(9):1047-58.

  An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one], was discovered in the authors'An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one], was discovered in the authors' laboratory as a novel type of tubulin-binding agent that mitigates polymerization dynamics of microtubule polymers without changing overall subunit-polymer equilibrium. To obtain systematic insight into the relationship between the structural framework of noscapine scaffold and its antitumor activity, the authors synthesized strategic derivatives (including two new ones in this article). The IC(50) values of these analogs vary from 1.2 to 56.0 µM in human acute lymphoblastic leukemia cells (CEM). Geometrical optimization was performed using semiempirical quantum chemical calculations at the 3-21G* level. Structures were in agreement with nuclear magnetic resonance analysis of molecular flexibility in solution and crystal structures. A genetic function approximation algorithm of variable selection was used to generate the quantitative structure activity relationship (QSAR) model. The robustness of the QSAR model (R(2) = 0.942) was analyzed by values of the internal cross-validated regression coefficient (R(2) (LOO) = 0.815) for the training set and determination coefficient (R(2) (test) = 0.817) for the test set. Validation was achieved by rational design of further novel and potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine. The experimentally determined value of pIC(50) for both the compounds (5.585 M) turned out to be very close to predicted pIC(50) (5.731 and 5.710 M).

• Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid-tubulin binding site.

  Authors: Pradeep K Naik, Seneha Santoshi, Ankit Rai, Harish C Joshi

  Journal of molecular graphics & modelling. 06/2011; 29(7):947-55.

  We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or nearWe have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: (1) in silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; (2) the molecular mechanics-generalized Born/surface area (MM-GB/SA) scoring results ΔΔG(bind-cald) for both noscapine and Br-noscapine (3.915 and 3.025 kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (ΔΔG(bind-Expt) of 3.570 and 2.988 kcal/mol, derived from K(d) values); and (3) Br-noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin.

• Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid.

  Authors: Pradeep K Naik, Biswa Prasun Chatterji, Surya N Vangapandu, Ritu Aneja, Ramesh Chandra, Srinivas Kanteveri, Harish C Joshi

  Journal of computer-aided molecular design. 05/2011; 25(5):443-54.

  Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (ΔG (bind)) of noscapinoids computed using linearNoscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (ΔG (bind)) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental ΔG (bind) with average root mean square error of 0.082 kcal/mol. This LIE-SGB model guided us in designing a novel derivative of noscapine, amino-noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted ΔG (bind) = -6.438 kcal/mol and experimental ΔG (bind) = -6.628 kcal/mol) than noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio. The modes of interaction of amino-noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct compared to noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different between both the lignads. The 'blind docking' approach (docking of ligand with different binding sites of a protein and their evaluations) as well as the reasonable accuracy of calculating ΔG (bind) using LIE-SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with colchicine-binding site or close to it. Our results revealed that amino-noscapine has better anti-tumor activity than noscapine.

• Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis.

  Authors: Pradeep K Naik, Seneha Santoshi, Harish C Joshi

  Journal of molecular modeling. 04/2011; 18(1):307-18.

  We have identified a new class of microtubule-binding compounds-noscapinoids-that alter microtubule dynamics at stoichiometric concentrations without affecting tubulin polymer mass. Noscapinoids showWe have identified a new class of microtubule-binding compounds-noscapinoids-that alter microtubule dynamics at stoichiometric concentrations without affecting tubulin polymer mass. Noscapinoids show great promise as chemotherapeutic agents for the treatment of human cancers. To investigate the structural determinants of noscapinoids responsible for anti-cancer activity, we tested 36 structurally diverse noscapinoids in human acute lymphoblastic leukemia cells (CEM). The IC(50) values of these noscapinoids vary from 1.2 to 56.0 μM. Pharmacophore models of anti-cancer activity were generated that identify two hydrogen bond acceptors, two aromatic rings, two hydrophobic groups, and one positively charged group as essential structural features. Additionally, an atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2) = 0.912, Q(2) = 0.908, Pearson R = 0.951) and effectively predicts the anti-cancer activity of training and test set compounds. The pharmacophore model presented here is well supported by electronic property analysis using density functional theory at B3LYP/3-21*G level. Molecular electrostatic potential, particularly localization of negative potential near oxygen atoms of the dimethoxy isobenzofuranone ring of active compounds, matched the hydrogen bond acceptor feature of the generated pharmacophore. Our results further reveal that all active compounds have smaller lowest unoccupied molecular orbital (LUMO) energies concentrated over the dimethoxy isobenzofuranone ring, azido group, and nitro group, which is indicative of the electron acceptor capacity of the compounds. Results obtained from this study will be useful in the efficient design and development of more active noscapinoids.

• Docking mode of delvardine and its analogues into the p66 domain of HIV-1 reverse transcriptase: screening using molecular mechanics-generalized born/surface area and absorption, distribution, metabolism and excretion properties.

  Authors: Dipankar Sengupta, Deeptak Verma, Pradeep K Naik

  Journal of biosciences. 01/2008; 32(7):1307-16.

  Delvardine and its structural derivatives are important non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). In this work,15 delvardine analogues were studied. A free energy-of-bindingDelvardine and its structural derivatives are important non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). In this work,15 delvardine analogues were studied. A free energy-of-binding (FEB)expression was developed in the form of an optimized linear combination of van der Waal (vdW), electrostatic, solvation and solvent-accessible surface area (SASA) energy terms. The solvation energy terms estimated by generalized born/surface area (GB/SA) play an important role in predicting the binding affinity of delvardine analogues. Out of 15 derivatives, substitution of CH3 with H at the Y and R positions, as well as substitution of SO2CH3 with only CH2 at the Z position in S2, S8 and S12 analogues, were found to be the most potent (glide score = -7.60, -8.06 and -7.44; pIC50 =7.28, 7.37 and 7.64) in comparison with the template delvardine (which is used currently as the drug candidate). All the three analogues also passed the absorption, distribution,metabolism and excretion (ADME) screening and Lipinski's rule of 5, and have the potential to be used for second-generation drug development. The work demonstrates that dock molecular mechanics-generalized born/surface area (MM-GB/SA-ADME) is a promising approach to predict the binding activity of ligands to the receptor and further screen for a successful candidate drug in a computer-aided rational drug design.

• Groundwater pollution around an industrial area in the coastal stretch of Maharashtra State, India.

  Authors: Pradeep K Naik, Biranchi N Dehury, Arun N Tiwari

  Environmental monitoring and assessment. 10/2007; 132(1-3):207-33.

  The main objective of this paper is to examine pollution threat, especially to the groundwater resources, around Tarapur industrial area (also called the Tarapur MIDC area) located on the Arabian SeaThe main objective of this paper is to examine pollution threat, especially to the groundwater resources, around Tarapur industrial area (also called the Tarapur MIDC area) located on the Arabian Sea Coast in Thane District of Maharashtra State, India and suggest remedial measures that may also be relevant to other industrial areas on the Indian Sea Coast. One hundred and thirty one samples were collected from various sources, such as dugwells, borewells, dug-cum-borewells, effluent sumps, drainage channels (effluent channels), creeks and ocean, for chemical analyses. These analyses show that the area in general is characterized by hard water and high salinity hazard, possibly due to its proximity and hydraulic connection with the sea. Although the potability of groundwater is questionable in certain pockets, it is good enough for irrigation purposes at present. Low pH value and high heavy metal contents in the adjoining Muramba creek water is a matter of great concern and may be attributed to the indiscriminate disposal of industrial effluents to the drainage channels connecting the creek. Muramba Creek is well connected with the Arabian Sea, and there are evidences of seawater intrusion around this creek. Because of the fact that Muramba Creek is highly polluted, and is hydraulically connected with the dugwells and borewells surrounding the creek, it cannot be ruled out that the groundwater around this creek is susceptible to contamination. Unless measures are not taken immediately to stop the indiscriminate disposal of the solid wastes and liquid effluents in open ground and drainage channels, and measures are not taken to maintain the appropriate pH values at the effluent treatment facilities before their disposal, the problem would indeed be formidable one day, and it will be too late then for the authorities to take care of the resulting maladies. Few suggestions have been given for controlling and managing the industrial pollution around the Tarapur MIDC area. These suggestions are relevant to other industrial areas situated on the 7,000 km long Indian Sea Coast.

• Assessment of genetic diversity among 16 promising cultivars of ginger using cytological and molecular markers.

  Authors: Sanghamitra Nayak, Pradeep K Naik, Laxmikanta Acharya, Arup K Mukherjee, Pratap C Panda, Premananda Das

  Zeitschrift für Naturforschung. C, Journal of biosciences. 60(5-6):485-92.

  Ginger (Zingiber officinale Roscoe) is an economically important plant, valued all over the world. The existing variation among 16 promising cultivars as observed through differential rhizome yieldGinger (Zingiber officinale Roscoe) is an economically important plant, valued all over the world. The existing variation among 16 promising cultivars as observed through differential rhizome yield (181.9 to 477.3 g) was proved to have a genetic basis using different genetic markers such as karyotype, 4C nuclear DNA content and random amplified polymorphic DNA (RAPD). The karyotypic analysis revealed a differential distribution of A, B, C, D and E type of chromosomes among different cultivars as represented by different karyotype formulas. A significant variation of 4C DNA content was recorded in ginger at an intraspecific level with values ranging from 17.1 to 24.3 pg. RAPD analysis revealed a differential polymorphism of DNA showing a number of polymorphic bands ranging from 26 to 70 among 16 cultivars. The RAPD primers OPC02, OPA02, OPD20 and OPN06 showing strong resolving power were able to distinguish all 16 cultivars. The extent of genetic diversity among these cultivars was computed through parameters of gene diversity, sum of allele numbers per locus and Shannon's information indices. Cluster analysis, Nei's genetic similarity and genetic distances, distribution of cultivars into special distance classes and principal coordinate analysis and the analysis of molecular variance suggested a conspicuous genetic diversity among different cultivars studied. The genetic variation thus detected among promising cultivars of ginger has significance for ginger improvement programs.

• Characterization of genetic structure of Podophyllum hexandrum populations, an endangered medicinal herb of Northwestern Himalaya, using ISSR-PCR markers and its relatedness with podophyllotoxin content

  Authors: Afroz Alam, Pradeep K. Naik, Pallavi Gulati, Ashwani Kumar Gulati, Gyan P. Mishra

  African Journal of Biotechnology (ISSN: 1684-5315) Vol 7 Num 8.

  To obtain accurate estimates of genetic structure for purpose of conservation planning for wild Indian May apple ( Podophyllum hexandrum ) in the Northwestern region of Himalayas, Himachal Pradesh,To obtain accurate estimates of genetic structure for purpose of conservation planning for wild Indian May apple ( Podophyllum hexandrum ) in the Northwestern region of Himalayas, Himachal Pradesh, genetic diversity among and within 28 populations were analyzed. Eleven microsatellite DNA markers were isolated and used to quantify genetic structure. Out of 68 ISSR loci tested, 88.23% were polymorphic. The genetic diversity was high (percentage of polymorphic bands, PBB = 83.82%; Shannon’s information index, I = 0.4413) at the population level, but low within individual study populations (PBB = 34.22%; Shannon’s information index I = 0.1879). The mean coefficient of gene differentiation (Gst) was 0.7484, indicating that 29.44% of the genetic diversity resided within the population. Analysis of molecular variance (AMOVA) indicated that 48% of the genetic diversity among the study populations was attributed to geographical location while 29% was attributed to differences in their habitats. An overall value of mean estimated number of gene flow (Nm = 0.1618) indicated that there was limited gene flow among the sampled populations. We found a clear tendency for higher Gst values and podophyllotoxin levels between the populations with increasing geographical altitude. However, the existing variation in podophyllotoxin content among the populations was proved to be coupled with geographical altitude (r = 0.922) but not with genetic variations (r = - 0.273). Hence we recommend that any further cultivation of this species requires optimization of environmental factors in order to increase the rate of production of podophyllotoxin from any collected population.