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Balupuri, Anand,Lee, Dae-Yon,Lee, Myeong Hwi,Chae, Sangeun,Jung, Eunmi,Kim, Yunki,Ryu, Jeonghee,Kang, Nam Sook Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.17
<P><B>Abstract</B></P> <P>The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds <B>20</B> and <B>21</B> significantly inhibited the ATX at low nanomolar level (IC<SUB>50</SUB> =2.99 and 2.19nM, respectively). Inhibitory activity of <B>21</B> was found to be slightly better than PF-8380 (IC<SUB>50</SUB> =2.80nM), which is one of the most potent ATX inhibitors reported till date. Furthermore, <B>21</B> displayed higher potency (IC<SUB>50</SUB> =14.99nM) than the first clinical ATX inhibitor, GLPG1690 (IC<SUB>50</SUB> =242.00nM) in the human plasma assay. Molecular docking studies were carried out to explore the binding pattern of newly synthesized compounds within active site of ATX. Docking studies suggested the putative binding mode of the novel compounds. Good ATX inhibitory activity of <B>21</B> was attributed to the hydrogen bonding interactions with Asn230, Trp275 and active site water molecules; electrostatic interaction with catalytic zinc ion and hydrophobic interactions with amino acids of the hydrophobic pocket.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of 4-phenyl-thiazole based compounds was designed and synthesized. </LI> <LI> Synthesized compounds exhibited promising inhibitory activity against ATX. </LI> <LI> Potent compound showed higher potency than clinical molecule in human plasma assay. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Discovery and optimization of ATX inhibitors via modeling, synthesis and biological evaluation
Balupuri, Anand,Lee, Myeong Hwi,Chae, Sangeun,Jung, Eunmi,Yoon, Woosub,Kim, Yunki,Son, So Jung,Ryu, Jeonghee,Kang, Dae-Hyuck,Yang, Young-Jae,You, Ji-Na,Kwon, Hyunjin,Jeong, Jong-Woo,Koo, Tae-Sung,Lee, Elsevier 2018 European journal of medicinal chemistry Vol.148 No.-
<P><B>Abstract</B></P> <P>Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (<B>2</B>, <B>3</B>, <B>4</B>, <B>12</B>, <B>13</B> and <B>14</B>) exhibited enhanced ATX inhibitory activities with IC<SUB>50</SUB> values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound <B>4</B> with IC<SUB>50</SUB> = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Novel ATX inhibitors were designed and synthesized based on our previous study. </LI> <LI> A number of compounds exhibited higher potency than the template molecule. </LI> <LI> Most potent compound showed good pharmacokinetic profile. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
A CoMFA Study of Quinazoline-based Anticancer Agents
Balupuri, Anand,Balasubramanian, Pavithra K.,Cho, Seung Joo The Basic Science Institute Chosun University 2015 조선자연과학논문집 Vol.8 No.3
Cancer has emerged as one of the leading cause of deaths worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of quinazoline-based anticancer agents. Purpose of the study is to understand the structural basis for their inhibitory activity. Comparative molecular field analysis (CoMFA) technique was employed to develop 3D-QSAR model. Ligand-based alignment scheme was used to generate a reliable CoMFA model. The model produced statistically significant results with a cross-validated correlation coefficient ($q^2$) of 0.589 and a non-cross-validated correlation coefficient ($r^2$) of 0.928. Model was further validated by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel and more potent anticancer agents.
Anand Balupuri,GADHECHANGDEV GORAKSHNATH,Pavithra K. Balasubramanian,Gugan Kothandan,조승주 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.8
The HIV-1 envelope glycoprotein gp120 playsa vital role in the entry of virus into the host cells and is apotential antiviral drug target. Recently, indole derivativeshave been reported to inhibit HIV-1 through binding togp120, and this prevents gp120 and CD4 interaction toinhibit the infectivity of HIV-1. In this work, moleculardocking, molecular dynamics (MD) and three-dimensionalquantitative structure–activity relationship studies werecarried out. Molecular docking studies of the most activeand the least active compounds were performed to identifyimportant residues in the binding pocket. We refined thedocked poses by MD simulations which resulted in conformationalchanges. After equilibration, the structure ofthe ligand and receptor complex was stable. Therefore, wejust took the last snapshot as the representative bindingpose for this study. This pose for the most active inhibitorwas used as a template for receptor-based alignment whichwas subsequently used for comparative molecular fieldanalysis. Resultant 3D contour maps suggested smaller substituents are desirable at the 7-position of indole ring toavoid steric interactions with Ser375, Phe382 and Tyr384residues in the active site. These results can be exploited todevelop potential leads and for structure-based drug designof novel HIV-1 inhibitors.
Balupuri, Anand,Cho, Seung Joo The Basic Science Institute Chosun University 2013 조선자연과학논문집 Vol.6 No.3
The HIV-1 envelope glycoprotein gp120 plays a vital role in the entry of the virus into the host cells. The crucial role of the glycoprotein suggests gp120 as potential drug target for the future antiviral therapies. Identification of the binding mode of small drug like compounds has been an important goal in drug design. In the current study we attempt to propose binding mode of indole derivatives in the binding pocket of gp120. These derivatives are reported to inhibit HIV-1 by acting as attachment inhibitors that bind to gp120 and prevent the gp120-CD4 interaction and thus inhibit the infectivity of HIV-1. To elucidate the molecular basis of the small molecules interactions to inhibit the glycoprotein function we employed the molecular docking simulation approach. This study provides insights to elucidate the binding pattern of indole-based gp120 inhibitors and may help in the rational design of novel HIV-1 inhibitors with improved potency.
A CoMFA Study of Glycogen Synthase Kinase 3 Inhibitors
Anand Balupuri, Pavithra K. Balasubramanian, Seung Joo Cho 조선대학교 기초과학연구원 2015 조선자연과학논문집 Vol.8 No.1
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a promising target in drug discovery. It is involved in multiple cellular processes and associated with the pathogenesis of several diseases. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of GSK- 3 inhibitors to understand the structural basis for inhibitory activity. Comparative molecular field analysis (CoMFA) method was used to derive 3D-QSAR models. A reliable CoMFA model was developed using ligand-based alignment scheme. The model produced statistically acceptable results with a cross-validated correlation coefficient (q2) of 0.594 and a non-cross-validated correlation coefficient (r2) of 0.943. Robustness of the model was checked by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel compounds with enhanced GSK-3 inhibitory activity.
Anand Balupuri,Pavithra K. Balasubramanian,조승주 대한약학회 2015 Archives of Pharmacal Research Vol.38 No.8
Vascular endothelial growth factor-2 receptor (VEGFR-2) kinase is a promising target for the development of novel anticancer drugs. Three-dimensional quantitative structure–activity relationship (3D-QSAR) study was performed on a series of tetrahydro-3H-imidazo[4,5c]pyridine derivatives to understand the structural basis for VEGFR-2 inhibitory activity. Several 3D-QSAR models were developed using various partial atomic charge schemes. Comparative molecular field analysis (CoMFA) and Comparative molecular similarity indices analysis (CoMSIA) methods were employed to derive these models. The CoMFA models performed better than the CoMSIA models. The reliable CoMFA model was obtained with the Gasteiger–Marsili charge scheme. The model produced statistically significant results with a cross-validated correlation coefficient (q2) of 0.635 and a coefficient of determination (r2) of 0.930. The model showed reasonable predictive power with predictive correlation coefficient (r2pred) of 0.582. Robustness of the model was further checked by leave-five-out cross-validation, bootstrapping and progressive scrambling analysis. The model was found to be statistically robust and expected to assist in the design of novel compounds with enhanced VEGFR-2 inhibitory activity.