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HQSAR Study on Substituted 1H-Pyrazolo[3,4-b]pyridines Derivatives as FGFR Kinase Antagonists
Bhujbal, Swapnil P.,Balasubramanian, Pavithra K.,Keretsu, Seketoulie,Cho, Seung Joo The Basic Science Institute Chosun University 2017 조선자연과학논문집 Vol.10 No.2
Fibroblast growth factor receptor (FGFR) belongs to the family of receptor tyrosine kinase. They play important roles in cell proliferation, differentiation, development, migration, survival, wound healing, haematopoiesis and tumorigenesis. FGFRs are reported to cause several types of cancers in humans which make it an important drug target. In the current study, HQSAR analysis was performed on a series of recently reported 1H-Pyrazolo [3,4-b]pyridine derivatives as FGFR antagonists. The model was developed with Atom (A) and bond (B) connection (C), chirality (Ch), hydrogen (H) and donor/acceptor (DA) parameters and with different set of atom counts to improve the model. A reasonable HQSAR model ($q^2=0.701$, SDEP=0.654, NOC=5, $r^2=0.926$, SEE=0.325, BHL=71) was generated which showed good predictive ability. The contribution map depicted the atom contribution in inhibitory effect. A contribution map for the most active compound (compound 24) indicated that hydrogen and nitrogen atoms in the side chains of ring B as well as hydrogen atoms in the side chain of ring C and the nitrogen atom in the ring D contributed positively to the activity in inhibitory effect whereas, the lowest active compound (compound 04) showed negative contribution to inhibitory effect. Thus results of our study can provide insights in the designing potent and selective FGFR kinase inhibitors.
HQSAR Study on Imidazo[1,2-b]pyridazine Derivatives as p38 MAP Kinase Antagonists
Bhujbal, Swapnil P.,Keretsu, Seketoulie,Cho, Seung Joo The Basic Science Institute Chosun University 2018 조선자연과학논문집 Vol.11 No.2
p38 MAP kinase belongs to the Mitogen-activated protein (MAP) kinase family; a serine/threonine kinase. It plays an important role in intracellular signal transduction pathways. It is associated with the development and progression of various cancer types making it a crucial drug target. Present study involves the HQSAR analysis of recently reported imidazo[1,2-b]pyridazine derivatives as p38 MAP kinase antagonists. The model was generated with Atom (A), bond (B), chirality (Ch), and hydrogen (H) parameters and with different set of atom counts to improve the model. An acceptable HQSAR model ($q^2=0.522$, SDEP=0.479, NOC=5, $r^2=0.703$, SEE=0.378, BHL=97) was developed which exhibits good predictive ability. A contribution map for the most active compound (compound 17) illustrated that hydrogen and nitrogen atoms in the ring A and ring B, as well as nitrogen atom in ring C and the hydrogen atom in the ring D provided positive activity in inhibitory effect while, the least active compound (compound 05) possessed negative contribution to inhibitory effect. Hence, analysis of produced HQSAR model can provide insights in the designing potent and selective p38 MAP kinase antagonists.
Structure elucidation of a newly isolated saponin from Clerodendrum serratum (L) Moon
Bhujbal, Santosh S.,K.Nanda, Rabindra,S.Deoda, Ramesh,Kumar, Dinesh,Kewatkar, Shailesh M.,S.More, Laxmikant,J.Patil, Manohar Kyung Hee Oriental Medicine Research Center 2010 Oriental pharmacy and experimental medicine Vol.10 No.4
Plant saponins are widely distributed amongst plants and have a wide range of biological properties. Icosahydropicenic acid, $C_{51}H_{80}O_{19}$ ((4S,6bS)-8a-((4,5-dihydroxy-6-methyl-3-((3R)-3,4,5-trihydroxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H-pyran-2-yloxy)carbonyl)-2-hydroxy-4, 6a, 6b, 11, 14b-pentamethyl-11-(2-methylprop-1-enyl)-3-(3,4,5-trihydroxy-6-(hydroxymethyl) - tetrahydro-2Hpyran-2-yloxy)-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-icosahydropicene-4-carboxylic acid), a new saponin was first time isolated from the roots of Clerodendrum Serratum (L) Moon (Verbenaceae). The structure elucidation of the compound was carried out by $^1H$ NMR and DART-MS studies.
Receptor-guided 3D-QSAR Study of Anilinoquinazolines as RET Receptor Tyrosine Kinase Antagonists
Swapnil Pandurang Bhujbal,Pavithra Kuruchi Balasubramanian,Seketoulie Keretsu,조승주 대한화학회 2019 Bulletin of the Korean Chemical Society Vol.40 No.3
A RET (Rearranged during transfection) kinase belongs to a receptor tyrosine kinase family. It plays a major role in development, maturation, survival, and maintenance of cells and tissues. Oncogenic activation of RET has been reported in numerous cancers. Thus, it is a significant therapeutic target for cancer. Present work covers docking and 3D-QSAR techniques executed on anilinoquinazoline derivatives as RET kinase antagonists. Docking study recognized important active site amino acid residues like Leu730, Gly731, Gly733, Glu734, Ala807, Gly810, Ser811, and Asp874 which inhibits the RET kinase. In 3D-QSAR technique, receptor-guided CoMFA (q2 = 0.723, NOC = 5, r2 = 0.980) as well as CoMSIA (q2 = 0.767, NOC = 6, r2 = 0.967) models were produced. The stabilities of these models were evaluated using diverse validation techniques. Contour maps showed that steric and hydrogen bond donor substitutions are favored at R1 and R2 positions whereas positive and negative substitutions are favored at the R1 position to enhance the potency. In addition, the substitution of H-bond accepting group to the region which is close to both phenyl and piperazine is favored. Hence, the outcome of this study could be beneficial to design more potent inhibitors for RET kinase.
Swapnil Pandurang Bhujbal,seketoulie keretsu,조승주 대한화학회 2019 Bulletin of the Korean Chemical Society Vol.40 No.8
Polo-like kinase-2 (PLK2) is a member of a highly conserved serine/threonine kinase family. PLK2 is implicated in the regulation of cell division. It is activated in the early G1 phase in cell cycle progression and is required for centriole duplication. It has been observed that the low expression of PLK2 leads to B-cell lymphoma and ovarian cancer. Furthermore, it was found to be associated with poor prognosis in non-small cell lung cancer, breast cancer, head and neck carcinoma, and osteosarcoma. Thus, PLK2 is considered as an important therapeutic target for cancer drug design due to its multiple roles in several types of cancers. In this work, molecular docking and 3D-QSAR techniques were performed on tetrahydropteridin derivatives as PLK2 inhibitors. Docking study identified crucial active site residues such as Leu88, Cys96, Ala109, Lys111, Val143, Leu159, Glu160, Cys162, and Phe212 which helps in the firm binding of the ligand. Receptor-guided CoMFA (q 2 = 0.859, NOC = 5, r 2 = 0.996) and CoMSIA (q 2 = 0.855, NOC = 6, r 2 = 0.998) models were produced. The predictability and stability of these models were assessed using different validation techniques. Contour maps revealed that electrostatic and steric substitutions were favorable at R1 and R2 positions respectively. In addition, the substitution of H-bond donor group at the R1 position was also favored. The results of this study could be helpful for designing more potent PLK2 inhibitors.
Structure elucidation of a newly isolated saponin from Clerodendrum serratum (L) Moon
Santosh S. Bhujbal,Rabindra K.Nanda,Ramesh S.Deoda,Dinesh Kumar,Shailesh M. Kewatkar,Laxmikant S.More,Manohar J.Patil 경희대학교 융합한의과학연구소 2010 Oriental Pharmacy and Experimental Medicine Vol.10 No.4
Plant saponins are widely distributed amongst plants and have a wide range of biological properties. Icosahydropicenic acid, C51H80O19 ((4S,6bS)-8a-((4,5-dihydroxy-6-methyl-3-((3R)-3,4,5-trihydroxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-tetrahydro-2H–pyran–2-yloxy)carbonyl)-2-hydroxy-4, 6a,6b, 11, 14b-pentamethyl-11-(2-methylprop-1-enyl)-3-(3,4,5-trihydroxy-6-(hydroxymethyl) - tetrahydro-2Hpyran-2-yloxy)-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 14, 14a, 14b-icosahydropicene-4-carboxylic acid), a new saponin was first time isolated from the roots of Clerodendrum Serratum (L)Moon (Verbenaceae).The structure elucidation of the compound was carried out by 1H NMR and DART-MS studies.
Seketoulie Keretsu,Swapnil Pandurang Bhujbal,조승주 대한화학회 2020 Bulletin of the Korean Chemical Society Vol.41 No.5
Janus Kinase 2 (JAK2) plays a vital role in the cytokine-mediated signaling pathway. Several experimental studies have shown that myeloproliferative neoplasms (MPNs) are associated with the overexpression of JAK2. Hence, JAK2 inhibition is considered to be vital for MPNs therapy. We have performed computational studies on 29 pyrimidin-2-aminopyrazol-hydroxamate-based JAK2 inhibitors. A comparative molecular field analysis (CoMFA) model (q2 = 0.6 and r2 = 0.94) was developed. Contour maps from the CoMFA model suggested that electronegative groups at the carbonyl and electropositive groups at the?hydroxyl were favored for JAK2 activity. Molecular docking and dynamics simulation revealed that the compound with highest activity (compound 13) formed electrostatic interactions with Leu932, Tyr934, Ser936, Asp939, and Tyr940 of JAK2. Binding free energy calculations showed that hydrophobic and H-bond interactions were the key contributors to the total binding. Results of this study could provide useful insights into designing new JAK2 inhibitors.