Changdev G Gadhe

Chosun University, Goyang, Gyeonggi, South Korea

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Publications (31)51.01 Total impact

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    ABSTRACT: Nociceptin receptor (NOPR) is an orphan G protein-coupled receptor that contains seven transmembrane helices. NOPR has a distinct mechanism of activation, though it shares a significant homology with other opioid receptors. Previously there were reports on homology modeling of NOPR and further molecular dynamics simulation studies for a short period. Recently the crystal structure of NOPR has been reported. In this study, we analyzed the time dependent behavior of NOPR docked with clinically important agonist molecules such as NOP (natural agonist) peptide and compound 10 (SCH-221510 derivative) using molecular dynamics simulations (MDS) for 100 ns. Molecular dynamics simulation of NOPR-agonist complexes allowed us to refine the system and also to identify stable structures with better binding modes. Structure activity relationships (SAR) for SCH221510 derivatives were investigated and reasons for the activities of these derivatives were determined. Our molecular dynamics trajectory analysis of NOPR-peptide and NOPR-compound 10 complexes found residues crucial for binding. Mutagenesis studies on the residues identified from our analysis could be effective. Our results could also provide useful information for structure-based drug design of novel and potent agonists targeting NOPR.
    Molecular BioSystems 09/2014; · 3.35 Impact Factor
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    ABSTRACT: Checkpoint kinase 1 (Chk1) is a promising target for the design of novel anticancer agents. In the present work, molecular docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on pyridyl aminothiazole derivatives as Chk1 inhibitors. AutoDock was used to determine the probable binding conformations of all the compounds inside the active site of Chk1. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed based on the docking conformations and alignments. The CoMFA model produced statistically significant results with a cross-validated correlation coefficient (q(2)) of 0.608 and a coefficient of determination (r(2)) of 0.972. The reliable CoMSIA model with q(2) of 0.662 and r(2) of 0.970 was obtained from the combination of steric, electrostatic and hydrogen bond acceptor fields. The predictive power of the models were assessed using an external test set of 14 compounds and showed reasonable external predictabilities (r(2)pred) of 0.668 and 0.641 for CoMFA and CoMSIA models, respectively. The models were further evaluated by leave-ten-out cross-validation, bootstrapping and progressive scrambling analyses. The study provides valuable information about the key structural elements that are required in the rational design of potential drug candidates of this class of Chk1 inhibitors.
    SAR and QSAR in Environmental Research 06/2014; · 1.67 Impact Factor
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    ABSTRACT: A protoberberine derivative library was used to search for selective inhibitors against kinases of the mitogen-activated protein kinase (MAPK) cascades in mammalian cells. Among kinases in mammalian MAPK pathways, we identified a compound (HWY336) that selectively inhibits kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4 and MKK7). The IC50 of HWY336 was 6 µM for MKK4 and 10 µM for MKK7 in vitro. HWY336 bound to both kinases reversibly via noncovalent interactions, and inhibited their activity by interfering with access of a protein substrate to its binding site. The binding affinity of HWY336 to MKK4 was measured by surface plasmon resonance to determine a dissociation constant (Kd) of 3.2 µM. When mammalian cells were treated with HWY336, MKK4 and MKK7 were selectively inhibited, resulting in inhibition of c-Jun NH2-terminal protein kinases in vivo. The structural model of HWY336 bound to either MKK4 or MKK7 predicted that HWY336 was docked to the activation loop, which is adjacent to the substrate binding site. This model suggested the importance of the activation loop of MKKs in HWY336 selectivity. We verified this model by mutating three critical residues within this loop of MKK4 to the corresponding residues in MKK3. The mutant MKK4 displayed similar kinase activity as wild-type kinase, but its activity was not inhibited by HWY336 compared to wild-type MKK4. We propose that the specific association of HWY336 to the activation loop of MKK4/MKK7 is responsible for its selective inhibition.
    PLoS ONE 01/2014; 9(4):e91037. · 3.53 Impact Factor
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    ABSTRACT: A series of novel coronands having a 2n-crown-n topology based on trioxane (6-crown-3) derivatives are designed and characterized. These neutral hosts can sense anions through pure aliphatic C-H hydrogen bonding (HB) in condensed phases due to the unusual topology of 2n-crown-n. C-H bonds are strongly polarized by two adjacent oxygen atoms in this scaffold. These hosts provide a rare opportunity to modulate anion binding strength by changing the electronic nature of aliphatic C-H bonds and offer ease of synthesis.
    Organic Letters 12/2013; · 6.14 Impact Factor
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    ABSTRACT: The HIV-1 envelope glycoprotein gp120 plays a vital role in the entry of virus into the host cells and is a potential antiviral drug target. Recently, indole derivatives have been reported to inhibit HIV-1 through binding to gp120, and this prevents gp120 and CD4 interaction to inhibit the infectivity of HIV-1. In this work, molecular docking, molecular dynamics (MD) and three-dimensional quantitative structure-activity relationship studies were carried out. Molecular docking studies of the most active and the least active compounds were performed to identify important residues in the binding pocket. We refined the docked poses by MD simulations which resulted in conformational changes. After equilibration, the structure of the ligand and receptor complex was stable. Therefore, we just took the last snapshot as the representative binding pose for this study. This pose for the most active inhibitor was used as a template for receptor-based alignment which was subsequently used for comparative molecular field analysis. Resultant 3D contour maps suggested smaller substituents are desirable at the 7-position of indole ring to avoid steric interactions with Ser375, Phe382 and Tyr384 residues in the active site. These results can be exploited to develop potential leads and for structure-based drug design of novel HIV-1 inhibitors.
    Archives of Pharmacal Research 12/2013; · 1.54 Impact Factor
  • Changdev G Gadhe, Gugan Kothandan, Seung Joo Cho
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    ABSTRACT: Chemokine receptor 5 (CCR5) is an integral membrane protein that is utilized during human immunodeficiency virus type-1 entry into host cells. CCR5 is a G-protein coupled receptor that contains seven transmembrane (TM) helices. However, the crystal structure of CCR5 has not been reported. A homology model of CCR5 was developed based on the recently reported CXCR4 structure as template. Automated docking of the most potent (14), medium potent (37), and least potent (25) CCR5 antagonists was performed using the CCR5 model. To characterize the mechanism responsible for the interactions between ligands (14, 25, and 37) and CCR5, membrane molecular dynamic (MD) simulations were performed. The position and orientation of ligands (14, 25, and 37) were found to be changed after MD simulations, which demonstrated the ability of this technique to identify binding modes. Furthermore, at the end of simulation, it was found that residues identified by docking were changed and some new residues were introduced in the proximity of ligands. Our results are in line with the majority of previous mutational reports. These results show that hydrophobicity is the determining factor of CCR5 antagonism. In addition, salt bridging and hydrogen bond contacts between ligands (14, 25, and 37) and CCR5 are also crucial for inhibitory activity. The residues newly identified by MD simulation are Ser160, Phe166, Ser180, His181, and Trp190, and so far no site-directed mutagenesis studies have been reported. To determine the contributions made by these residues, additional mutational studies are suggested. We propose a general binding mode for these derivatives based on the MD simulation results of higher (14), medium (37), and lower (25) potent inhibitors. Interestingly, we found some trend for these inhibitors such as, salt bridge interaction between basic nitrogen of ligand and acidic Glu283 seemed necessary for inhibitory activity. Also, two aromatic pockets (pocket I - TM1-3 and pocket II - TM3-6) were linked by the central polar region in TM7, and the simulated inhibitors show important interactions with the Trp86, Tyr89, Tyr108, Phe112, Ile198, Tyr251, Leu255, and Gln280 and Glu283 residues. These results shed light on the usage of MD simulation to identify more stable, optimal binding modes of the inhibitors.
    Journal of biomolecular Structure & Dynamics 11/2013; 31(11):1251-1276. · 2.98 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) is a phenomenon whereby cancer cells experience intrinsic or acquired resistance to a broad spectrum of structurally and functionally distinct chemotherapeutic agents. Permeability glycoprotein (P-gp) is the key protein responsible for the development of MDR in cancer cells, as it exports chemotherapeutic agents from cells. In the present study, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) techniques were used to derive predictive models for phenylsulfonylfuroxan derivatives as P-gp inhibitors. Cross-validated correlation coefficients (q2) of 0.811, 0.855, and 0.907 and non-cross-validated correlation coefficients (r2) of 0.87, 0.985, and 0.973 were obtained for CoMFA, CoMSIA, and HQSAR derived models, respectively. The predictive power of the models were assessed using an external test set of five compounds and showed reasonable external predictabilities (r2pred) of 0.704, 0.517, and 0.713, respectively. Contour and atomic contribution maps were generated to investigate physicochemical requirements of ligands for better receptor binding affinity. 3D Contour maps suggested molecular interactions such as steric and electrostatic effects and hydrogen bond formation. However, atomic contribution maps indicated that ortho and para positions of the R1 phenylsulfonyl ring are the most desirable regions to modulate P-gp antagonism. The 3rd and 4th positions of the central five-membered ring were also found to be important. Our results are in line with previous reports. Information obtained from the contour and atomic contribution maps were utilized to design more potent compounds containing different R1 fragments. In addition, the activities of these more potent compounds were predicted using derived models.
    Anti-cancer agents in medicinal chemistry 09/2013;
  • Changdev Gorakshnath Gadhe, Gugan Kothandan, Seung Joo Cho
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    ABSTRACT: Human immunodeficiency virus type-1 (HIV-1) is a causative agent of Acquired immunodeficiency syndrome (AIDS), which has affected a large population of the world. Viral envelope glycoprotein (gp120) is an intrinsic protein for HIV-1 to enter into human host cells. Molecular docking guided molecular dynamics (MD) simulation was performed to explore the interaction mechanism of heterobiaryl derivative with gp120. MD simulation result of inhibitor-gp120 complex demonstrated stability. Our MD simulation results are consistent with most of the previous mutational and modeling studies. Inhibitor has an interaction with the CD4 binding region. Van der Waals interaction between inhibitor and Val255, Thr257, Asn425, Met426 and Trp427 were important. This preliminary MD model could be useful in exploiting heterobiaryl-gp120 interaction in greater detail, and will likely to shed lights for further utilization in the development of more potent inhibitors.
    Bulletin- Korean Chemical Society 08/2013; 34(8):2466-2472. · 0.84 Impact Factor
  • Changdev G Gadhe, Gugan Kothandan, Seung Joo Cho
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    ABSTRACT: P-glycoprotein (P-gp) is responsible for the multidrug resistance (MDR) and involved in the expulsion of xenobiotics out of cell. In this paper, homology modeling, docking and molecular dynamics simulation (MDS) was performed for the human P-gp desmosdumotin inhibitor. Docking study was carried out in the P-gp nucleotide binding domain 2 (NBD2). The desmosdumotin binding region occupied the ATP binding region (flavonoid binding region) with hydrophobic and hydrophilic interactions. Analysis of root mean square deviations (RMSDs) of active site residues indicated the binding site residues were stable throughout the simulation period. As shown in previous results with structurally similar flavonoid compounds, van der Waals and electrostatic interactions were found to be important factors for the desmosdumotin-NBD2 inhibition. Docking results suggest that desmosdumotin interacts with the NBD2 through both hydrogen bonds (Lys1076, Ser1077 and Thr1078) and hydrophobic interactions (Tyr1044, Val1052, Gly1073 and Cys1074). In addition, the involvement of other amino-acids was identified via MDS (Lys1076 and Ser1077 for hydrogen bonds and Tyr1044, Val1052, Gly1073, Cys1074 and Gly1075 for hydrophobic interactions). Thus, current preliminary model of interactions between desmosdumotin-NBD2 could be helpful to understand the in-depth inhibition mechanism of P-gp at NBD2 level and to design more potent inhibitors which could effectively overcome MDR of anticancer agents.
    Anti-cancer agents in medicinal chemistry 06/2013;
  • Changdev G. Gadhe, Gugan Kothandan, Seung Joo Cho
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    ABSTRACT: P-glycoprotein (P-gp) is responsible for the multidrug resistance (MDR) and involved in the expulsion of xenobiotics out of cell. In this paper, homology modeling, docking and molecular dynamics simulation (MDS) was performed for the human P-gp desmosdumotin inhibitor. Docking study was carried out in the P-gp nucleotide binding domain 2 (NBD2). The desmosdumotin binding region occupied the ATP binding region (flavonoid binding region) with hydrophobic and hydrophilic interactions. Analysis of root mean square deviations (RMSDs) of active site residues indicated the binding site residues were stable throughout the simulation period. As shown in previous results with structurally similar flavonoid compounds, van der Waals and electrostatic interactions were found to be important factors for the desmosdumotin-NBD2 inhibition. Docking results suggest that desmosdumotin interacts with the NBD2 through both hydrogen bonds (Lys1076, Ser1077 and Thr1078) and hydrophobic interactions (Tyr1044, Val1052, Gly1073 and Cys1074). In addition, the involvement of other amino-acids was identified via MDS (Lys1076 and Ser1077 for hydrogen bonds and Tyr1044, Val1052, Gly1073, Cys1074 and Gly1075 for hydrophobic interactions). Thus, current preliminary model of interactions between desmosdumotin-NBD2 could be helpful to understand the in-depth inhibition mechanism of P-gp at NBD2 level and to design more potent inhibitors which could effectively overcome MDR of anticancer agents.
    Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) 06/2013; · 2.61 Impact Factor
  • Gugan Kothandan, Changdev G Gadhe, Seung Joo Cho
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    ABSTRACT: In this study, we report on modeling of Galanin receptor type 3 (Gal3 ) and its interaction with agonist and antagonists using in silico methodologies. Comparative structural modeling of Gal3 were based on multiple templates. With the availability of reported selective Gal3 antagonists, docking was done into the predicted binding site. Similarly, galanin, a reported agonist, was also modeled and then docked into the receptor's active site. CoMFA models were developed using ligand based (q2 = 0.537, r2 = 0.961, noc = 5,) and receptor guided (docked mode 1: q2 = 0.574, r2 = 0.946, noc = 5) and docked pose based (q2 = 0.499, r2 = 0.954, noc = 5) alignment schemes. CoMFA contour analysis revealed that, bulky substitution around the meta position of the phenyl ring, as well as optimal substitution (para) of the phenyl ring could produce molecules with improved activity. We also found that Gln79, Ile82, Asp86, Trp88, His99, Ile102, Tyr103, Glu170, Pro174, Ala175, Asp185, Arg273, His277 and Tyr281 are crucial and mutational studies on these residues could be helpful. The results obtained from this study can further be exploited for structure based drug design and also help the researchers to identify novel antagonists targeting Gal3 . © 2013 John Wiley & Sons A/S.
    Chemical Biology &amp Drug Design 03/2013; · 2.47 Impact Factor
  • Changdev G Gadhe, Gugan Kothandan, Seung Joo Cho
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    ABSTRACT: Chemokine receptor 5 (CCR5) is an important receptor used by human immunodeficiency virus type 1 (HIV-1) to gain viral entry into host cell. In this study, we used a combined approach of comparative modeling, molecular docking, and three dimensional quantitative structure activity relationship (3D-QSAR) analyses to elucidate detailed interaction of CCR5 with their inhibitors. Docking study of the most potent inhibitor from a series of compounds was done to derive the bioactive conformation. Parameters such as random selection, rational selection, different charges and grid spacing were utilized in the model development to check their performance on the model predictivity. Final comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were chosen based on the rational selection method, Gasteiger-Hückel charges and a grid spacing of 0.5 Å. Rational model for CoMFA (q (2) = 0.722, r (2) = 0.884, Q (2) = 0.669) and CoMSIA (q (2) = 0.712, r (2) = 0.825, Q (2) = 0.522) was obtained with good statistics. Mapping of contour maps onto CCR5 interface led us to better understand of the ligand-protein interaction. Docking analysis revealed that the Glu283 is crucial for interaction. Two new amino acid residues, Tyr89 and Thr167 were identified as important in ligand-protein interaction. No site directed mutagenesis studies on these residues have been reported.
    Archives of Pharmacal Research 01/2013; · 1.54 Impact Factor
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    Changdev G. Gadhe, Seung Joo Cho
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    ABSTRACT: In this manuscript, we report a protocol to determine most of the lowest energy conformations from the ensemble of conformations. 12-crown-4 was taken as study compound to get the most of energy minima conformations. Molecular dynamic (MD) simulation for 1 nanosecond (ns) was performed at 300, 500, 700, 900 and 1100 K temperature. At particular interval conformations were sampled. Then Gaussian program was used to minimize compounds using PM6 energy levels. Duplicates were removed by checking energy as well as mirror image conformations, and only unique conformations were retained for the next level minimization. It was observed that upto certain increment in temperature the number of unique conformations were increased, but afterword it decreased.
    Journal of the Chosun Natural Science. 01/2013; 6(1).
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    Gugan Kothandan, Changdev G. Gadhe, Seung Joo Cho
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    ABSTRACT: Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane helices. Recent pharmaceutical research has focused on the antagonism of CCR2 and candidate drugs are currently undergoing clinical studies for the treatment of diseases like arthritis, multiple sclerosis, and type 2 diabetes. In this study, we analyzed the time dependent behavior of CCR2 docked with a potent 4-azetidinyl-1-aryl-cyclohexane (4AAC) derivative using molecular dynamics simulations (MDS) for 20 nanoseconds (ns). Homology modeling of CCR2 was performed and the 4AAC derivative was docked into this binding site. The docked model of selected conformations was then utilized to study the dynamic behavior of the 4AAC enzyme complexes inside lipid membrane. MDS of CCR2-16b of 4AAC complexes allowed us to refine the system since binding of an inhibitor to a receptor is a dynamic process and identify stable structures and better binding modes. Structure activity relationships (SAR) for 4AAC derivatives were investigated and reasons for the activities were determined. Probable binding pose for some CCR2 antagonists were determined from the perspectives of binding site. Initial modeling showed that Tyr49, Trp98, Ser101, Glu291, and additional residues are crucial for 4AAC binding, but MDS analysis showed that Ser101 may not be vital. 4AAC moved away from Ser101 and the hydrogen bonding between 4AAC and Ser101 vanished. The results of this study provide useful information regarding the structure-based drug design of CCR2 antagonists and additionally suggest key residues for further study by mutagenesis.
    Bulletin- Korean Chemical Society 01/2013; 34(11). · 0.84 Impact Factor
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    Changdev G. Gadhe, Seung Joo Cho
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    ABSTRACT: Human P-gp is a protein responsible for the multidrug resistance (MDR) and causes failure of cancer chemotherapy. Till date no X-ray crystal structure is reported for this membrane protein, which hampers active research in the field. We performed homology modeling to develop three dimensional (3D) model of P-gp, and docking studies of the verapamil and curcumin have been performed to gain insight into the interaction mechanism between inhibitors and P-gp. It was identified that the inhibitors docked into the upper part of P-gp and interacted through the hydrophobic interactions.
    Journal of the Chosun Natural Science. 01/2013; 6(4).
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    ABSTRACT: Multidrug resistance (MDR) plays a crucial role in the failure of cancer treatment with chemotherapeutic agents. In order to overcome the MDR, we have developed both 2D and 3D-QSAR models to enhance the structural requirement for P-gp inhibitors. In this work, hologram quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of arylmethylamine-phenyl derivatives of P-gp inhibitors. The best predictions were obtained for HQSAR model (q 2 = 0.645, r 2 = 0.772), CoMFA model (q 2 = 0.577, r 2 = 0.917), and CoMSIA model (electrostatic, and H-bond donor) (q 2 = 0.610, r 2 = 0.923). Statistical parameters from the generated QSAR models indicated that the data is well fitted and have high predictive ability. HQSAR result showed that donor and acceptor descriptors play an important role in P-gp activity, and methoxy group on the A-ring at R1 position is necessary for increasing activity. The CoMFA and CoMSIA models predicted that steric, electrostatic, and H-bond donor parameters are important for activity toward P-gp. Our theoretical results could be useful to design novel and more potent P-gp derivatives.
    Medicinal Chemistry Research 09/2012; 22(5):2511-2523. · 1.61 Impact Factor
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    ABSTRACT: p38 kinase plays a vital role in inflammation mediated by tumor necrosis factor-a and interleukin-1b pathways. Inhibition of p38 kinase provides an effective way to treat inflammatory diseases. 3D-QSAR study was performed to obtain reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for a series of p38 inhibitors with three different alignment methods (Recep-tor based, atom by atom matching, and pharmacophore based). Among the different alignment methods, better statistics were obtained with receptor-based alignment (CoMFA: q 2 = 0.777, r 2 = 0.958; CoMSIA: q 2 = 0.782, r 2 = 0.927). Superposing CoMFA/CoMSIA contour maps on the p38 active site gave a valuable insight to understand physical factors which are important for binding. In addi-tion, this pharmacophore model was used as a 3D query for virtual screening against NCI database. The hit compounds were further filtered by docking and scoring, and their biological activities were predicted by CoMFA and CoMSIA models.
    Medicinal Chemistry Research 08/2012; · 1.61 Impact Factor
  • Changdev G Gadhe, Gugan Kothandan, Seung Joo Cho
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    ABSTRACT: Partial atomic charge is a useful concept to describe physico-chemical properties of a molecule. For this, various schemes have been devised to get reasonable values. Mutagen X is an ideal set to test the effect of partial atomic charge variation. Therefore, we collected data from previous reports and studied various charge schemes. Our systematic study covers 26 charge calculation schemes along with a broad range of levels of theory. Charge calculation schemes include charges from charge equalisation, electrostatic potential fitting, molecular orbital and atomic polar tensor. Calculation levels span from empirical, semi-empirical, Hartree – Fock, density functional and Møller – Plesset 2. We also used two validation statistics for internal prediction. To observe the electrostatic effect accurately during comparative molecular field analysis (CoMFA) modelling, we first studied isolated electrostatic parameters to avoid interaction effect with steric parameters. The results clearly show that adding steric parameters does change statistical conclusions as well as CoMFA maps. Although there was a weak trend that quantum mechanical (QM)-derived charges gave better statistical values, it is not apparent statistically (alpha ¼ 0.05). Particularly, Mülliken population analysis (MPA) did not produce better results. Therefore, when we excluded MPA schemes from QM calculation, the QM-derived charges were found to be significant, i.e. sophisticated charge schemes other than MPA with QM methods were found to be superior to simple empirical charge schemes. In addition, we demonstrated that in order to test charge schemes properly, excluding steric parameter is more important. This work exemplifies Occam's theorem of parsimony. A simpler model is a better model.
    Molecular Simulation 01/2012; · 1.06 Impact Factor
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    Changdev G. Gadhe
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    ABSTRACT: The resistance of tumour cells against cytotoxic drug is significant limitation in successful chemotherapeutic treatment of cancer. To date, no crystal structure is available for human P-gp. We developed homology model for human P-gp NBD2 by using coordinates of transporter associated protein (TAP1). Docking study was performed for 8-geranyl-chrysin (Flavonoids) inhibitor in the NBD2 model. Ligand-protein interactions were determined which indicates that the 8-geranyl chrysin shares two overlapping sites in the cytosolic domains of P-gp, the ATP site and a hydrophobic steroid-binding site.
    Journal of the Chosun Natural Science. 01/2012; 5(1).
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    Changdev G. Gadhe, Seung Joo Cho
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    ABSTRACT: Multidrug resistance is a major obstacle in cancer chemotherapy. Cancer cells efflux chemotherapeutic drug out of cell by means of transporter and reduce the active concentration of it inside cell. Such transporters are member of the ATP binding cassettes (ABC) protein. It includes P-gp, multiple resistant protein (MRP), and breast cancer resistant protein (BCRP). These proteins are widely distributed in the human cells such as kidney, lung, endothelial cells of blood brain barrier etc. However, there are number of drugs developed for it, but most of them are getting transported by it. So, still there is necessity of a good modulator, which could effectively combat the transport of chemotherapeutic agents. Natural products origin modulators were found to be effective against transporter such as flavonoids, which belongs to third generation modulators. They have advantage over synthetic inhibitor in the sense that they have simple structure and abundant in nature. This review focuses on the P-gp structure its architecture, efflux mechanism, herbal inhibitors and their mechanism of action.
    Journal of the Chosun Natural Science. 01/2012; 5(2).