Hologram Quantitative Structure-Activity Relationships Study of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl} Urea Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors

Keretsu, Seketoulie,Balasubramanian, Pavithra K.,Bhujbal, Swapnil P.,Cho, Seung Joo The Basic Science Institute Chosun University 2017 조선자연과학논문집 Vol.10 No.3

Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis, which is the formation of new blood vessels from pre-existing vessels. Consequently, blocking of the vascular endothelial growth factor receptor (VEGFR-2) by small molecule inhibitors leads to the inhibition of cancer induced angiogenesis. In this study, we performed a two dimensional quantitative structure activity relationship (2D-QSAR) study of 38 N-Phenyl-N'-{4-(4-quinolyloxy) phenyl} urea derivatives as VEGFR-2 inhibitors based on hologram quantitative structure-activity (HQSAR). The model developed showed reasonable $q^2=0.521$ and $r^2=0.932$ values indicating good predictive ability and reliability. The atomic contribution map analysis of most active compound (compound 7) indicates that hydrogen and oxygen atoms in the side chain of ring A and oxygen atom in side chain of ring C contributes positively to the activity of the compounds. The HQSAR model developed and the atomic contribution map can serve as a guideline in designing new compounds for VEGFR-2 inhibition.

Hologram Quantitative Structure-Activity Relationships Study of N-Phenyl-N’-{4-(4-quinolyloxy)phenyl} Urea Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors

Seketoulie Keretsu,Pavithra K. Balasubramanian,Swapnil P. Bhujbal,Seung Joo Cho 조선대학교 기초과학연구원 2017 조선자연과학논문집 Vol.10 No.3

Receptor-guided 3D-Quantitative Structure–Activity Relationship and Docking Studies of 6-Substituted 2-Arylaminopurines as CDK2 Kinase Inhibitors

Seketoulie Keretsu,Pavithra Kuruchi Balasubramanian,Swapnil Pandurang Bhujbal,조승주 대한화학회 2017 Bulletin of the Korean Chemical Society Vol.38 No.11

Cyclin-dependent kinase 2 (CDK2) plays important roles in cell cycle regulation. Owing to its multiple roles in many cancer types, it is considered as a significant target for cancer drug design. In this study, we used docking techniques and 3D-quantitative structure–activity relationship (3D-QSAR) studies on a series of 6-substituted 2-arylaminopurine derivatives as CDK2 kinase inhibitors. Receptor-guided comparative molecular field analysis (CoMFA) (q2 = 0.653, optimal number of component [ONC] = 6, r2 = 0.965) and comparative molecular similarity indices analysis (CoMSIA) (q2 = 0.718, ONC = 6, r2 = 0.872) models were developed. Validation by progressive scrambling, bootstrapping (BS), and leave-five-out method suggests that the developed 3D-QSAR models (CoMFA and CoMSIA) have reasonable predictive ability and reliability. Docking analysis revealed five hydrogen bond interactions between the compound 13 (most active compound) and CDK2 active site residues namely Glu81, Leu83, and Asp86. Contour map analysis gave comprehensive information regarding favorable and unfavorable substitution groups. Bulky, electropositive, and hydrophobic substitution groups at the R2 region can enhance the inhibitory activity of compounds whereas electronegative, hydrogen bond donor, and nonhydrophobic substitution groups at the position R1 will increase the inhibitory activity. Our contour map results can be used as a guideline in designing new potent compounds for CDK2 inhibition.

Computational Study of Pyrimidin-2-Aminopyrazol-Hydroxamatebased JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

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.

3D-QSAR, Docking and Molecular Dynamics Simulation Study of C-Glycosylflavones as GSK-3β Inhibitors

Ghosh, Suparna,Keretsu, Seketoulie,Cho, Seung Joo The Basic Science Institute Chosun University 2020 조선자연과학논문집 Vol.13 No.4

Abnormal regulation, hyperphosphorylation, and aggregation of the tau protein are the hallmark of several types of dementia, including Alzheimer's Disease. Increased activity of Glycogen Synthase Kinase-3β (GSK-3β) in the Central Nervous System (CNS), increased the tau hyperphosphorylation and caused the neurofibrillary tangles (NFTs) formation in the brain cells. Over the last two decades, numerous adenosine triphosphate (ATP) competitive inhibitors have been discovered that show inhibitory activity against GSK-3β. But these compounds exhibited off-target effects which motivated researchers to find new GSK-3β inhibitors. In the present study, we have collected the dataset of 31 C-Glycosylflavones derivatives that showed inhibitory activity against GSK-3β. Among the dataset, the most active compound was docked with the GSK-3β and molecular dynamics (MD) simulation was performed for 50 ns. Based on the 50 ns MD pose of the most active compound, the other dataset compounds were sketched, minimized, and aligned. The 3D-QSAR based Comparative Molecular Field Analysis (CoMFA) model was developed, which showed a reasonable value of q2=0.664 and r2=0.920. The contour maps generated based on the CoMFA model elaborated on the favorable substitutions at the R2 position. This study could assist in the future development of new GSK-3β inhibitors.

HQSAR Study on Imidazo[1,2-b]pyridazine Derivatives as p38 MAP Kinase Antagonists

Swapnil P. Bhujbal,Seketoulie Keretsu,Seung Joo Cho 조선대학교 기초과학연구원 2018 조선자연과학논문집 Vol.11 No.2

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.

A Combined Molecular Docking and 3D-QSAR Studies on Tetrahydropteridin Derivatives as PLK2 Antagonists

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.

Computational Modeling of Novel Phosphoinositol-3-kinase γ Inhibitors Using Molecular Docking, Molecular Dynamics, and 3D-QSAR

Suparna Ghosh,Seketoulie Keretsu,Seung Joo Cho 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.8

Phosphoinositol-3-kinase ? (PI3K?) is a member of the class-IB PI3K superfamily and plays a significant role in G-protein-coupled receptor mediated cell signaling. Recent studies have suggested that elevated expression of PI3K? in tumor-associated macrophages strongly influences immune suppression and tumor growth. Due to the presence of many isoforms of PI3K, the selective inhibition of PI3K? remains challenging. Therefore, it is necessary to design more potent inhibitors against PI3K? for cancer treatment. In this study, we have reported the critical interactions of isoindolinone-based inhibitors with PI3K? by docking and molecular dynamics simulations. The binding free energy of the receptor-ligand complex was calculated using molecular mechanics/Poison-Boltzmann surface area approach. We have performed the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) to determine the structure?activity relationship of the inhibitors. The CoMFA (q2 = 0.681 and r2 = 0.968) and CoMSIA (q2 = 0.665 and r2 = 0.982) models showed reasonable predictive ability. Thereafter, the contour maps derived from CoMFA and CoMSIA were used to design several new compounds, among which, the compound D04 showed high predicted activity values. The designed compound was subjected to absorption-distribution-metabolism-excretion/toxicity prediction and synthetic accessibility analyses. Our results could provide theoretical guidance for the future development of new PI3K? inhibitors.

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.