Design, synthesis, docking and biological evaluation of 4-phenyl-thiazole derivatives as autotaxin (ATX) inhibitors

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>

Exploration of the Binding Mode of Indole Derivatives as Potent HIV-1 Inhibitors Using Molecular Docking Simulations

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 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.

A CoMFA Study of Glycogen Synthase Kinase 3 Inhibitors

Balupuri, Anand,Balasubramanian, Pavithra K.,Cho, Seung Joo The Basic Science Institute Chosun University 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 ($q^2$) of 0.594 and a non-cross-validated correlation coefficient ($r^2$) 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.

Comparative Molecular Field Analysis of Pyrrolopyrimidines as LRRK2 Kinase Inhibitors

Balupuri, Anand,Balasubramanian, Pavithra K.,Cho, Seung Joo The Basic Science Institute Chosun University 2016 조선자연과학논문집 Vol.9 No.1

Leucine rich repeat kinase 2 (LRRK2) is a highly promising target for Parkinson's disease (PD) that affects millions of people worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of pyrrolopyrimidine-based selective LRRK2 kinase inhibitors. This study was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. A reliable 3D-QSAR model was developed using comparative molecular field analysis (CoMFA) technique. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$) of 0.539 and a non-cross-validated correlation coefficient ($r^2$) of 0.871. Robustness of the model was further evaluated by bootstrapping and progressive scrambling analysis. This work could assist in designing more potent LRRK2 inhibitors.

Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors

Balupuri, Anand,Balasubramanian, Pavithra K.,Cho, Seung Joo The Basic Science Institute Chosun University 2016 조선자연과학논문집 Vol.9 No.3

The p21-activated kinase-1 (PAK1) has emerged as a potential target for anticancer therapy. It is overexpressed in ovarian, breast and bladder cancers. This suggests that PAK1 may contribute to tumorigenesis. 4-azaindole derivatives are reported as potent PAK1 inhibitors. The present work deals with the molecular docking studies of 4-azaindoles with PAK1. Probable binding mode of these inhibitors has been identified by molecular modeling. Docking results indicated that hydrogen bonding interactions with Glu345 and Leu347 are responsible for governing inhibitor potency of the compounds. Additionally, Val284, Val328, Met344 and Leu396 were found to be accountable for hydrophobic interactions inside the active site of PAK1.

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>

In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study

Balupuri, Anand,Gadhe, Changdev G.,Balasubramanian, Pavithra K.,Kothandan, Gugan,Cho, Seung Joo 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.8

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.

Determination of structural requirements of Mer kinase inhibitors and binding interaction analysis using in silico approaches

Balupuri, A.,Balasubramanian, P. K.,Cho, S. J. Springer Science + Business Media 2016 Medicinal chemistry research Vol.25 No.12

<P>Mer kinase is implicated as therapeutic target for the prevention and treatment of thrombosis. A molecular modeling study was performed on a series of pyrimidine-based inhibitors of Mer specific tyrosine kinase. The relationship between the structure and the activity of these inhibitors was studied using three-dimensional quantitative structure-activity relationship, molecular docking and molecular dynamics simulations. A reliable comparative molecular similarity indices analysis model with a cross-validated correlation coefficient (q (2)) of 0.637 and a conventional correlation coefficient (r (2)) of 0.955 was obtained from the combination of steric and hydrogen bond donor fields. Model showed acceptable predictive capability with predicted correlation coefficient (r (2) (pred)) of 0.614. Satisfactory performance in several validation procedures indicated the reliability and robustness of the model. Docking study was performed to determine the binding mode of these inhibitors inside the active site of Mer kinase. Molecular dynamics simulation was performed on the docked structure to explore the thorough binding process. Docking and molecular dynamics simulation identified some crucial binding residues such Leu593, Pro672, Phe673, Met674, Gly677, Asp678, Thr681, Tyr685, and Met730. This study provides useful information for the design of novel and more potent antithrombotic agents.</P>

Computational Analysis of Pyridopyrimidine-based Polo Like Kinase 2 (PLK2) Inhibitors: Examining the Structural Basis for Anticancer Activity

Balupuri, Anand,K. Balasubramanian, Pavithra,Joo Cho, Seung BENTHAM SCIENCE PUBLISHERS LTD 2017 LETTERS IN DRUG DESIGN AND DISCOVERY Vol.14 No.5