• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.18
• /
• pp.8191-8196
• /
• 2016

Inhibition of EGFR-EGF interactions forms an important therapeutic rationale in treatment of non-small cell lung carcinoma. Established inhibitors have been successful in reducing proliferative processes observed in NSCLC, however patients suffer serious side effects. Considering the narrow therapeutic window of present EGFR inhibitors, the present study centred on identifying high efficacy EGFR inhibitors through structure based virtual screening strategies. Established inhibitors - Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib formed parent compounds to retrieve similar compounds by linear fingerprint based tanimoto search with a threshold of 90%. The compounds (parents and respective similars) were docked at the EGF binding cleft of EGFR. Patch dock supervised protein-protein interactions were established between EGF and ligand (query and similar) bound and free states of EGFR. Compounds ADS103317, AKOS024836912, AGN-PC-0MXVWT, GNF-Pf-3539, SCHEMBL15205939 were retrieved respectively similar to Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib. Compound-AGN-PC-0MXVWT akin to Erlotinib showed highest affinity against EGFR amongst all the compounds (parent and similar) assessed in the study. Further, AGN-PC-0MXVWT brought about significant blocking of EGFR-EGF interactions in addition showed appreciable ADMET properties and pharmacophoric features. In the study, we report AGN-PC-0MXVWT to be an efficient and high efficacy inhibitor of EGFR-EGF interactions identified through computational approaches.

• Bulletin of the Korean Chemical Society
• /
• v.34 no.12
• /
• pp.3553-3558
• /
• 2013

The three dimensional-quantitative structure activity relationship (3D-QSAR) studies on chemical features of pyridine-2-amines in the external region of c-Met active site (ER chemical features of pyridine-2-amines) were conducted by docking, comparative molecular field analysis (CoMFA), and topomer CoMFA methods. The CoMFA model obtained the partial least-squares (PLS) statistical results, cross-validated correlation coefficient ($q^2$) of 0.703, non cross-validated correlation coefficient ($r^2$) of 0.947 with standard error of estimate (SEE) of 0.23 and the topomer CoMFA obtained $q^2$ of 0.803, $r^2$ of 0.940, and SEE of 0.24. Further, the test set was applied to validate predictive abilities of models, where the predictive $r^2$ ($r{^2}_{pred}$) for CoMFA and topomer CoMFA models were 0.746 and 0.608, respectively. Each contribution of ER chemical features of pyridine-2-amines to the inhibitory potency showed correlation coefficients, $r^2$ of 0.670 and 0.913 for two core parts, 3-(benzo[d]oxazol-2-yl)pyridine-2-amine and 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy) pyridine-2-amine, respectively, with corresponding experimental $pIC_{50}$.

• Tuberculosis and Respiratory Diseases
• /
• v.80 no.3
• /
• pp.255-264
• /
• 2017

Background:N-acetyl transferase (NAT) inactivates the pro-drug isoniazid (INH) to N-acetyl INH through a process of acetylation, and confers low-level resistance to INH in Mycobacterium tuberculosis (MTB). Similar to NAT of MTB, NAT2 in humans performs the same function of acetylation. Rapid acetylators, may not respond to INH treatment efficiently, and could be a potential risk factor, for the development of INH resistance in humans. Methods: To understand the contribution of NAT of MTB and NAT2 of humans in developing INH resistance using in silico approaches, in this study, the wild type (WT) and mutant (MT)-NATs of MTB, and humans, were modeled and docked, with substrates and product (acetyl CoA, INH, and acetyl INH). The MT models were built, using templates 4BGF of MTB, and 2PFR of humans. Results: On the basis of docking results of MTB-NAT, it can be suggested that in comparison to the WT, binding affinity of MT-G207R, was found to be lower with acetyl CoA, and higher with acetyl-INH and INH. In case of MT-NAT2 from humans, the pattern of score with respect to acetyl CoA and acetyl-INH, was similar to MT-NAT of MTB, but revealed a decrease in INH score. Conclusion: In MTB, MT-NAT revealed high affinity towards acetyl-INH, which can be interpreted as increased formation of acetyl-INH, and therefore, may lead to INH resistance through inactivation of INH. Similarly, in MT-NAT2 (rapid acetylators), acetylation occurs rapidly, serving as a possible risk factor for developing INH resistance in humans.

• Journal of Korea Game Society
• /
• v.9 no.1
• /
• pp.93-103
• /
• 2009

A Serious Game helps the learners to recognize the problems effectively, grasp and classify important information needed to solve the problems and convey the contents of what they have learned. Owing not only to this game-like fun but also to the educational effect, The Serious Game can be usefully applied to education and training in the areas of scientific technology and industrial technology. This study proposes the Serious Game that users can apply to biotechnology by using intuitive multi-modal interfaces. In this study, a stereoscopic monitor is used to make three dimensional molecular structures, and multi-modal interface is used to efficiently control. Based on a such system, this study easily solved the docking simulation function, which is one of the important experiments, by applying these game factors. For this, we suggested the level-up concept as a game factor that depends on numbers of objects and users. The proposed system was evaluated in performance comparison in result time of a new drug design process on AIDS virus with previous approach.

• Proceedings of the Korean Society for Bioinformatics Conference
• /
• 2004.11a
• /
• pp.181-190
• /
• 2004

The docking and in silico ligand screening procedures can select small sets of lead -like candidates from large libraries of either commercially or synthetically available compounds; however, the vast number of such molecules make the potential size of this task enormous. To accelerate the discovery of drugs to inhibit several targets, we have exploited massively distributed computing to screen compound libraries virtually. The Korea@HOME project was launched in Feb. 2002, and one year later, more than 1200 PC's have been recruited. This has created a 31 -gigaflop machine that has already provided more than 1400 hours of CPU time. It has all owed databases of millions of compounds to be screened against protein targets in a matter of days. Now, the virtual screening software suitable for distributed environments is developed by BMD. It has been evaluated in terms of the accuracy of the scoring function and the search algorithm for the correct binding mode.

• Archives of Reconstructive Microsurgery
• /
• v.14 no.1
• /
• pp.37-41
• /
• 2005

Purpose: The purpose of this study was to evaluate the effectiveness of internal transport using Ilizarov apparatus with free flap surgery for infected tibial nonunion. Materials and Methods: We reviewed 8 patients of infected tibial nonunion treated with internal transport using Ilizarov apparatus and free flap surgery. Seven of eight patients were available for at least 1 year follow-up. All patients were male. The mean age at the time of the surgery was All fractures were Gustilo's type III B open fracture. The mean length of the bone defect was 8.5 cm. All used flaps for covering the soft tissue defect were free rectus abdominis muscle flap. We evaluated bone and functional results with use of the Paley and Catagni's classification. And we classified the complication with use of the Paley's classification. Results: Acceptable length and solid union of bone was achieved in all cases. The mean size of the bone length was 7.2 cm. The mean healing index was 69.5 days/cm. All but one case needed bone graft at docking site. All flaps were survived. There was no recurrence of infection. According to Paley and Catagni's classification, all cases showed excellent or good results. Complications were pin tract infection in 3 cases, persistent pain in 2 cases and limitation of joint motion in 2 cases. Conclusion: Simultaneous free-tissue transfer and Ilizarov distraction osteogenesis was thought to be an attractive treatment modality for infected nonunion of the tibia.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.9
• /
• pp.3759-3765
• /
• 2015

Background: Approaches in disruption of MDM2-p53 interactions have now emerged as an important therapeutic strategy in resurrecting wild type p53 functional status. The present study highlights virtual screening strategies in identification of high affinity small molecule non-peptidic inhibitors. Nutlin3A and RG7112 belonging to compound class of Cis-imidazoline, MI219 of Spiro-oxindole class and Benzodiazepine derived TDP 665759 served as query small molecules for similarity search with a threshold of 95%. The query molecules and the similar molecules corresponding to each query were docked at the transactivation binding cleft of MDM2 protein. Aided by MolDock algorithm, high affinity compound against MDM2 was retrieved. Patch Dock supervised Protein-Protein interactions were established between MDM2 and ligand (query and similar) bound and free states of p53. Compounds with PubCid 68870345, 77819398, 71132874, and 11952782 respectively structurally similar to Nutlin3A, RG7112, Mi219 and TDP 665759 demonstrated higher affinity to MDM2 in comparison to their parent compounds. Evident from the protein-protein interaction studies, all the similar compounds except for 77819398 (similar to RG 7112) showed appreciable inhibitory potential. Of particular relevance, compound 68870345 akin to Nutlin 3A had highest inhibitory potential that respectively showed 1.3, 1.2, 1.16 and 1.26 folds higher inhibitory potential than Nutilin 3A, MI 219, RG 7112 and TDP 1665759. Compound 68870345 was further mapped for structure based pharamacophoric features. In the study, we report Cis-imidazoline derivative compound; Pubcid: 68870345 to have highest inhibitory potential in blocking MDM2-p53 interactions hitherto discovered.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.7
• /
• pp.4347-4352
• /
• 2013

Aim: To investigate the molecular mechanisms underlying triggering of apoptosis by hesperetin using in silico and in vitro methods. Methods: The mechanism of binding of hesperetin with NF-${\kappa}B$ and other apoptotic proteins like BAX, BAD, $BCL_2$ and $BCL_{XL}$ was analysed in silico using Schrodinger suite 2009. In vitro studies were also carried out to evaluate the potency of hesperetin in inducing apoptosis using the human prostate cancer PC-3 cell line. Results: Hesperetin was found to exhibit high-affinity binding resulting from greater intermolecular forces between the ligand and its receptor NF-${\kappa}B$ (-7.48 Glide score). In vitro analysis using MTT assay confirmed that hesperetin reduced cell proliferation ($IC_{50}$ values of 90 and $40{\mu}M$ at 24 and 48h respectively) in PC-3 cells. Hesperetin also downregulated expression of the anti-apoptotic gene $BCL_{XL}$ at both mRNA and protein levels and increased the expression of pro-apoptotic genes like BAD at mRNA level and BAX at mRNA as well as protein levels. Conclusion: The results suggest that hesperetin can induce apoptosis by inhibiting NF-${\kappa}B$.

• Proceedings of the Korea Committee for Ocean Resources and Engineering Conference
• /
• 2006.11a
• /
• pp.347-350
• /
• 2006

Maritime and Ocean Engineering Research Institute (MOERI), a branch of KORDI, has designed and manufactured a model of an autonomous underwater vehicle (AUV) named ISiMI(Integrated Submergible for Intelligent Mission Implementation). ISiMI is an AUV platform to satisfy the various needs of experimental test required for development of challenging technologies newly investigated in the field of underwater robot; control and navigational algorithms and software architectures. The main design goal of ISiMI AUV is downsizing which will reduce substantially the operating cost compared to other vehicles previously developed in KORDI such as VORAM or DUSAUV. As a result of design and manufacturing process, ISiMI is implemented to be 1.2m in length, 0.17m in diameter and weigh 20 kg in air. A series of tank test is conducted to verify the basic functions of ISiMI in the Ocean Engineering Basin of MOERI, which includes manual control with R/F link, auto depth, auto heading control and a final approach control for underwater docking. This paper describes the implementation of ISiMI system and the experimental results to verify the function of ISiMi as a test-bed AUV platform.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.5
• /
• pp.2027-2033
• /
• 2014

Background: We aimed to assess RET proto-oncogene polymorphisms in three different Iranian families with medullary thyroid cancer (MTC), and performed molecular dynamics simulations and free energy stability analysis of these mutations. Materials and Methods: This study consisted of 48 patients and their first-degree relatives with MTC confirmed by pathologic diagnosis and surgery. We performed molecular dynamics simulations and free energy stability analysis of mutations, and docking evaluation of known RET proto-oncogene inhibitors, including ZD-6474 and ponatinib, with wild-type and mutant forms. Results: The first family consisted of 27 people from four generations, in which nine had the C.G2901A (P.C634Y) mutation; the second family consisted of six people, of whom three had the C.G2901T (P.C634F) mutation, and the third family, who included 12 individuals from three generations, three having the C.G2251A (P.G691S) mutation. The automated 3D structure of RET protein was predicted using I-TASSER, and validated by various protein model verification programs that showed more than 96.3% of the residues in favored and allowed regions. The predicted instability indices of the mutated structures were greater than 40, which reveals that mutated RET protein is less thermo-stable compared to the wild-type form (35.4). Conclusions: Simultaneous study of the cancer mutations using both in silico and medical genetic procedures, as well as onco-protein inhibitor binding considering mutation-induced drug resistance, may help in better overcoming chemotherapy resistance and designing innovative drugs.