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Lee, Ju-Hyeon,El-Damasy, Ashraf K.,Seo, Seon Hee,Gadhe, Changdev G.,Pae, Ae Nim,Jeong, Nakcheol,Hong, Soon-Sun,Keum, Gyochang Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.21
<P><B>Abstract</B></P> <P>Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-<I>d</I>]pyrimidine octamides (<B>4a</B>–<B>o</B> and <B>6a</B>–<B>g</B>) and their corresponding free amines <B>5a</B>–<B>m</B> and <B>7a</B>–<B>g</B> have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides <B>6d</B>–<B>g</B> as well as the amine derivative <B>7b</B> have shown the best anticancer activity with single digit micromolar GI<SUB>50</SUB> values over the tested cancer cells, and low cytotoxic effects (GI<SUB>50</SUB> > 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-<I>d</I>]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member <B>6f</B> was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI<SUB>50</SUB> and TGI values over multiple cancer cells. Kinase profile of compound <B>6f</B> over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of <B>6f</B> against TrkA (IC<SUB>50</SUB> = 2.25 µM), FGFR4 (IC<SUB>50</SUB> = 6.71 µM) and Tie2 (IC<SUB>50</SUB> = 6.84 µM) was explained by molecular docking study, which also proposed that <B>6f</B> may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound <B>6f</B> may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Synthesis and <I>in vitro</I> antiproliferative activities of new pyrrolo[2,3-<I>d</I>]pyrimidines are reported. </LI> <LI> Compounds <B>6d–g</B> exerted single digit micromolar GI<SUB>50</SUB> values over the tested cancer cell lines. </LI> <LI> Compound <B>6f</B> has selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. </LI> <LI> Compound <B>6f</B> may be a type III allosteric kinase inhibitor. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Investigation of Binding Modes of the Verapamil and Curcumin into Human P-glycoprotein (P-gp)
Gadhe, Changdev G.,Cho, Seung Joo The Basic Science Institute Chosun University 2013 조선자연과학논문집 Vol.6 No.4
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.
Importance of Silicon Atom in the Drug Design Process
Gadhe, Changdev G.,Cho, Seung Joo The Basic Science Institute Chosun University 2012 조선자연과학논문집 Vol.5 No.4
The pharmaceutical industry has an ongoing need for new, safe medicines with genuine biomedical effects. Most of the candidate molecules are far from becomes a drug, because of their pharmacokinetic and pharmacodynamic properties. The introduction of bioisostere to improve properties of molecules and to obtain new class of compound is currently increased. Silicon substitution of carbon of existing drugs is an attractive strategy to search a new candidate with improved biological and physicochemical properties. The fundamental differences between carbon and silicon can lead to improved profile of the silicon containing candidate, and could be exploited to get further benefit in drug design process.
CoMFA vs. Topomer CoMFA, which One is better a Case Study with 5-Lipoxygenase Inhibitors
Gadhe, Changdev G. The Basic Science Institute Chosun University 2011 조선자연과학논문집 Vol.4 No.2
Quantitative structure-activity relationships (QSAR) have been applied for two decades in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. The fundamental principle underlying the QSAR is that the structural difference is responsible for the variations in biological activities of the compounds. In this work, we developed 3D-QSAR model for a series of 5-Lipoxygenase inhibitors, utilizing comparative molecular field analysis (CoMFA) and Topomer CoMFA methodologies. Our developed models addressed superiority of Topomer CoMFA over CoMFA. The CoMFA model was obtained with $q^2$=0.593, $r^2$=0.939, $Q^2$=0.334 with 6 optimum number of components (ONC). Higher statistical results were obtained with the Topomer CoMFA model ($q^2$=0.819, $r^2$=0.947, ONC=5). Further robustness of developed models was checked with the ANOVA test and it shows F=113 for CoMFA and F=162.4 for Topomer CoMFA model. Contour map analysis indicated that the more requirement of electrostatic parameter for improved potency.
Binding site exploration of CCR5 using in silico methodologies: a 3D-QSAR approach
Changdev G. Gadhe,Gugan Kothandan,조승주 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.1
Chemokine receptor 5 (CCR5) is an importantreceptor used by human immunodeficiency virus type 1(HIV-1) to gain viral entry into host cell. In this study, weused a combined approach of comparative modeling,molecular docking, and three dimensional quantitativestructure activity relationship (3D-QSAR) analyses toelucidate detailed interaction of CCR5 with their inhibitors. Docking study of the most potent inhibitor from a series ofcompounds was done to derive the bioactive conformation. Parameters such as random selection, rational selection,different charges and grid spacing were utilized in themodel development to check their performance on themodel predictivity. Final comparative molecular fieldanalysis (CoMFA) and comparative molecular similarityindices analysis (CoMSIA) models were chosen based onthe rational selection method, Gasteiger-Hu¨ckel chargesand a grid spacing of 0.5 A ° . Rational model for CoMFA(q2 = 0.722, r2 = 0.884, Q2 = 0.669) and CoMSIA(q2 = 0.712, r2 = 0.825, Q2 = 0.522) was obtained withgood statistics. Mapping of contour maps onto CCR5interface led us to better understand of the ligand–proteininteraction. Docking analysis revealed that the Glu283 iscrucial for interaction. Two new amino acid residues, Tyr89 and Thr167 were identified as important in ligand–protein interaction. No site directed mutagenesis studies onthese residues have been reported.
Flavonoids: An Emerging Lead in the P-glycoprotein Inhibition
Changdev G. Gadhe, Seung Joo Cho 조선대학교 기초과학연구원 2012 조선자연과학논문집 Vol.5 No.2
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. Key words : Human P-gp, Anticancer,