• 통합자연과학논문집
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• 제9권1호
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• pp.41-61
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• 2016

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Phosphoinositide 3-kinases (PI3Ks) play important role in Non-Small Cell Lung Cancer. PI3Ks constitute a lipid kinase family which modulates the function of numerous substrates involved in the regulation of cell survival, cell cycle progression and cellular growth. Herein, we describe the ligand based pharmacophore combined with molecular docking studies methods to identify new potent PI3K inhibitors. Several pharmacophore models were generated and validated by Guner-Henry scoring Method. The best models were utilized as 3D pharmacophore query to screen against ZINC database (Chemical and Natural) and the retrieved hits were further validated by fitness score, Lipinski's rule of five. Finally four compounds were found to have good potential and they may act as novel lead compounds for PI3K inhibitor designing.

• Bulletin of the Korean Chemical Society
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• 제33권1호
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• pp.149-152
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• 2012

The (S)-(+)-decursin and its analogues are reported as potent inhibitors of melanin production in B16 murine melanoma cells. In order to understand the factors responsible for potency as well as inhibition of potency of (S)-(+)-decursin and its analogues, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Since receptor structures are not available, a pharmacophore model was constructed. Using PHASE, we generated 3 different models and selected the seven-site model, which returned excellent statistical values ($r^2$ = 0.9127, $Q^2$ = 0.6878, Pearson-R = 0.9014). Using the generated pharmacophore model, we screened a natural products library and obtained 4'-epi-decursin as the most related compound. 4'-epidecursin is similar to (S)-(+)-decursin, but shows additional interaction possibilities with tyrosinase. The study thus sheds some light on possibility of developing more potent tyrosinase inhibitors.

• Asian Pacific Journal of Cancer Prevention
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• 제16권18호
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• pp.8307-8311
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• 2016

Lung cancer is one particular type of cancer that is deadly and relatively common than any other. Treatment is with chemotherapy, radiation therapy and surgery depending on the type and stage of the disease. Focusing on drugs used for chemotherapy and their associated side effects, there is a need to design and develop new anti-lung cancer drugs with minimal side effects and improved efficacy. The pharmacophore model appears to be a very helpful tool serving in the designing and development of new lead compounds. In this paper, pharmacophore analysis of 10 novel anti-lung cancer compounds was validated for the first time. Using LigandScout the pharmacophore features were predicted and 3D pharmacophores were extracted via VMD software. A training set data was collected from literature and the proposed model was applied to the training set whereby validating and verifying similar activity as that of the most active compounds was achieved. Therefore pharmacophore develoipment could be recommended for further studies.

• Bulletin of the Korean Chemical Society
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• 제29권3호
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• pp.656-662
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• 2008

Antagonists of the d -opioid receptor are effective in overcoming resistance against analgesic drugs such as morphine. To identify novel antagonists of the d -opioid receptor that display high potency and low resistance, we performed 3D-QSAR analysis using chemical feature-based pharmacophore models. Chemical features for d -opioid receptor antagonists were generated using quantitative (Catalyst/HypoGen) and qualitative (Catalyst/HipHop) approaches. For HypoGen analysis, we collected 16 peptide and 16 non-peptide antagonists as the training set. The best-fit pharmacophore hypotheses of the two antagonist models comprised identical features, including a hydrophobic aromatic (HAR), a hydrophobic (HY), and a positive ionizable (PI) function. The training set of the HipHop model was constructed with three launched opioid drugs. The best hypothesis from HipHop included four features: an HAR, an HY, a hydrogen bond donor (HBD), and a PI function. Based on these results, we confirm that HY, HAR and PI features are essential for effective antagonism of the d -opioid receptor, and determine the appropriate pharmacophore to design such antagonists.

• Bulletin of the Korean Chemical Society
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• 제29권3호
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• pp.647-655
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• 2008

Microsomal prostaglandin E2 synthase (mPGES-1) is a potent target for pain and inflammation. Various QSAR (quantitative structure activity relationship) analyses used to understand the factors affecting inhibitory potency for a series of MK886 analogues. We derived four QSAR models utilizing various quantum mechanical (QM) descriptors. These QM models indicate that steric, electrostatic and hydrophobic interaction can be important factors. Common pharmacophore hypotheses (CPHs) also have studied. The QSAR model derived by best-fitted CPHs considering hydrophobic, negative group and ring effect gave a reasonable result (q2 = 0.77, r2 = 0.97 and Rtestset = 0.90). The pharmacophore-derived molecular alignment subsequently used for 3D-QSAR. The CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) techniques employed on same series of mPGES-1 inhibitors which gives a statistically reasonable result (CoMFA; q2 = 0.90, r2 = 0.99. CoMSIA; q2 = 0.93, r2 = 1.00). All modeling results (QM-based QSAR, pharmacophore modeling and 3D-QSAR) imply steric, electrostatic and hydrophobic contribution to the inhibitory activity. CoMFA and CoMSIA models suggest the introduction of bulky group around ring B may enhance the inhibitory activity.

• Bulletin of the Korean Chemical Society
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• 제34권10호
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• pp.2909-2914
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• 2013

p-Hydroxyphenylpyruvate dioxygenase (HPPD) is a potent herbicide target that is in current use. In this study, we developed a predictive pharmacophore model that uses known HPPD inhibitors based on a theoretically constructed HPPD homology model. The pharmacophore model derived from the three-dimensional (3D) structure of a target protein provides helpful information for analyzing protein-ligand interactions, leading to further improvement of the ligand binding affinity.

• 대한화학회지
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• 제57권1호
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• pp.99-103
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• 2013

The present communication deals with the Pharmacophore modeling, 3D QSAR and docking analysis on series of Pyrimidine derivatives as potential calcium channel blockers. The computational studies showed hydrogen bond donor, hydrogen bond acceptor, and hydrophobic group are important features for calcium channel blocking activity. These studies showed that Pyrimidine scaffold can be utilized for designing of novel calcium channels blockers for CVS disorders.

• Bulletin of the Korean Chemical Society
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• 제34권7호
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• pp.1972-1984
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• 2013

Microtubules play an important role in intracellular transport, mobility, and particularly mitosis. Paclitaxel (Taxol$^{TM}$) and paclitaxel-like compounds have been shown to be anti-tumor agents useful for various human tumors. Paclitaxel-like compounds operate by stabilizing microtubules through interface binding at the interface between two ${\beta}$-tubulin monomers in adjacent protofilaments. In this paper we present the elucidation of the structural features of paclitaxel and paclitaxel-like compounds (e.g., epothilones) with microtubule stabilizing activities, and relate their activities to spatial and chemical features of the molecules. CATALYST program was used to generate three-dimensional quantitative structure activity relationships (3D-QSARs) resulting in 3D pharmacophore models of epothilone- and paclitaxel-derivatives. Pharmacophore models were generated from diverse conformers of these compounds resulting in a high correlation between experimental and predicted biological activities (r = 0.83 and 0.91 for epothilone and paclitaxel derivatives, respectively). On the basis of biological activities of the training sets, five- and four-feature pharmacophore hypotheses were generated in the epothilone and paclitaxel series. The validation of generated hypotheses was achieved by using twelve epothilones and ten paclitaxels, respectively, which are not in the training sets. The clustering (grouping) and merging techniques were used in order to supplement spatial restrictions of each of hypothesis and to develop more comprehensive models. This approach may be of use in developing novel inhibitor candidates as well as contributing a better understanding of structural characters of many compounds useful as anticancer agents targeting microtubules.

• 대한화학회지
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• 제54권4호
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• pp.363-373
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• 2010

마약인 모르핀, 헤로인, 코데인, 펜타조신 그리고, 버프레노파인에 대하여 범밀도함수이론에 근거하여 계산 연구를 수행하였다. 약물특이 분자단과 치환기의 기하학적 파라미터는 B3LYP/6-31+G(d) 레벨로 계산하였고, 전자의 구조는B3LYP/6-311++G(d,p) 레벨로 같은 혼성 범함수를 사용하여 계산하였다. 원자의 전하분포는 Mulliken 개체 수 분석에 의하여 구하였다. 보고된 생물학적 활성, 계산된 분배 계수, 전자 및 기하학적 분석을 토대로 펜타조신과 버프레노파인을 새로 제시된 유사화합물에 대한 모델화합물로 선택하였으며, 이들 유사화합물에 대하여 연구한 뒤, 모델화합물과 비교하였다. 본 연구 결과는 약물특이 분자단의 기하학적 구조와 전자 구조가 다른 치환기의 존재 하에서도 변함없이 유지된다는 것을 보여주었다. 제시된 유사화합물들도 모델 분자의 특성을 갖고 있기 때문에, 이들 유사화합물들도 생물학적 활성을 나타낼 것 같다.

• Bulletin of the Korean Chemical Society
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• 제35권7호
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• pp.2097-2108
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• 2014

Chemical feature based quantitative pharmacophore models were generated using the HypoGen module implemented in DS2.5. The best hypothesis, Hypo1, which was characterized by the highest correlation coefficient (0.96), the highest cost difference (61.60) and the lowest RMSD (0.74), consisted of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic and one ring aromatic. The reliability of Hypo1 was validated on the basis of cost analysis, test set, Fischer's randomization method and GH test method. The validated Hypo1 was used as a 3D search query to identify novel inhibitors. The screened molecules were further refined by employing ADMET, docking studies and visual inspection. Three compounds with novel scaffolds were selected as the most promising candidates for the designing of Mcl-1 antagonists. Finally, a 10 ns molecular dynamics simulation was carried out on the complex of receptor and the retrieved ligand to demonstrate that the binding mode was stable during the MD simulation.