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Pseudoreceptor: Concept and an Overview
Kothandan, Gugan,Madhavan, Thirumurthy,Gadhe, Changdev G.,Cho, Seung Joo The Basic Science Institute Chosun University 2010 조선자연과학논문집 Vol.3 No.3
A pseudoreceptor combines structure-based and ligand-based techniques to represent a unifying concept for both receptor mapping and ligand matching. In this molecular modeling approach, there are opportunities to construct the pseudoreceptor models using a set of small molecules. To build a reliable pseudoreceptor model, we need a set of ligand molecules with known affinity (biological activity) to generate 3D bioactive conformation for each of these ligand molecules. Several software packages are available to generate a pseudoreceptor model and this can provide an entry point for structure based drug discovery in cases where receptor structure information is not available. In this review, we presented the concept of pseudoreceptor, as well as discussed about various software packages available to generate a pseudoreceptor model.
Kothandan, Gugan The Basic Science Institute Chosun University 2011 조선자연과학논문집 Vol.4 No.3
Tuberculosis is a major health problem in humans because of its multidrug resistance and discovering new treatments for this disease is urgently required. The synthesis of isoprenoids in Mycobacterium tuberculosis has been reported as an interesting pathway to target. In this context, 2C-methyl-D-erythritol 4-phosphate (MEP) pathway of M. tuberculosis has drawn attention. The MEP pathway begins with the condensation of glyceraldehyde 3-phosphate and pyruvate forming 1-deoxy-D-xylulose 5-phosphate (DXP) which is catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS). As there is no X-ray structure was reported for this target, comparative modeling was used to generate the three dimensional structure. The structure was further validated by PROCHECK, VERIFY-3D, PROSA, ERRAT and WHATIF. Molecular docking studies was performed with the substrate (Thiamine pyrophosphate) and the reported inhibitor 2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolol[1,5-a]pyrimidin-7-one) against the developed model to identify the crucial residues in the active site. This study may further be useful to provide structure based drug design.
Kothandan, Gugan,Ganapathy, Jagadeesan,Damodharan, Kannan,Sanmargam, Aravindhan The Basic Science Institute Chosun University 2014 조선자연과학논문집 Vol.7 No.2
The crystal structure of the title compounds with both coumarin and sulfonamide moieties were examined. These two groups have very special for their pharmaceutical and medicinal properties have been determined from single crystal X-ray diffraction data. In the title compound crystallizes in the monoclinic space group C2/c with unit cell dimension a = 28.633(3) ${\AA}$, b= 9.3215(7) ${\AA}$ and c= 24.590(2) ${\AA}$ [alpha & gamma=$90^{\circ}$ beta= $115.976(3)^{\circ}$]. In the structure The S1 atom shows a distorted tetrahedral geometry, with O1-S1-O2 [119.74 $(2)^{\circ}$] and N1-S1-C5 [$105.57(1)^{\circ}$] angles deviating from ideal tetrahedral values are attributed to the Thrope-Ingold effect. The sum of bond angles around N1 ($316.2(1)^{\circ}$) indicates that N1 is in sp2 hybridization. The Pyridine ring adopts boat conformation and pyran rings adopt a sofa conformation. The carboxylate group of atoms were disordered over two positions with site occupancy factors 0.598 (9):0.402 (9). Crystal structure and packing is stabilized by $C-H{\ldots}O$ intra and inter molecular hydrogen bond interactions.
A Short Review on Human Functional Neuropeptide Y Receptors
Kothandan, Gugan,Cho, Seung Joo The Basic Science Institute Chosun University 2012 조선자연과학논문집 Vol.5 No.2
Neuropeptide Y (NPY), a 36-amino acid polypeptide, is a member of the pancreatic polypeptide family, which consists of NPY, peptide YY (PYY) and pancreatic polypeptide (PP). The neuropeptide Y (NPY) receptors called Y receptors belongs to G-protein coupled that are involved in a variety of physiological functions such as appetite regulation, circadian rhythm and anxiety. Five receptor subtypes have been cloned in mammals (Y1, Y2, Y4, Y5, and Y6) of which four are functional. In this short review, information about the functional NYP receptors was analyzed. Sequence analyses were done between these receptors to identify the relationships between them. Phylogram was generated between these receptors to identify the close homologue between these receptors. Our sequence analyses found that Y1 and Y4 receptors are close than the other receptors. Further structure based analysis could be useful to identify subtype selective antagonists and dual antagonists targeting Y1 and Y4 receptors.
Kothandan, Gugan The Basic Science Institute Chosun University 2012 조선자연과학논문집 Vol.5 No.3
Gal (1-3) receptors are members of GPCR superfamily with seven transmembrane helices. The neuropeptide galanin mediates its effects through the receptor subtypes Gal1, Gal2, and Gal3 and has been implicated in anxiety and depression related behaviors. Galanin receptors are considered to be important targets for the development of novel antidepressant drugs. Owing to the importance of these receptors, a short communication about the sequential and structural studies about the functional Galanin (1-3) receptors has been reported. Structural studies have been hampered due to the lack of X-ray crystal structures. However with the availability of templates with close homologs comparative modeling could be encouraging. Sequence analysis was done for each receptors and homology modeling of each receptors were done with recently reported templates. Comparative analyses were done between these receptors to identify the relationships between them sequentially. Phylogram was generated between these receptors to identify the close homologue between this receptor and found that Gal2 and Gal3 receptors are closer. Our results could be useful for further structure based drug design targeting Gal1, Gal2 and Gal3 receptors.
Kothandan, Gugan The Basic Science Institute Chosun University 2012 조선자연과학논문집 Vol.5 No.1
Chemokine receptor antagonists have potential applications in field of drug discovery. Although the chemokine receptors are G-protein-coupled receptors, their cognate ligands are small proteins (8 to 12 kDa), and so inhibiting the ligand/receptor interaction has been challenging. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, targeting both CCR2 and CCR5 could be a useful strategy. Because of the importance of these receptors, providing information regarding the binding site is of prime importance. Herein, we report the comparison of CCR2 of CCR5 binding sites both sequentially as well as structurally. We also urged the importance of crucial residues in the binding site, to facilitate the development of dual antagonists targeting both the receptors. These results could also be useful for the design of novel and potent dual CCR2 and CCR5 antagonists using structure based drug design.
A Review about the Importance of Protonation of Ionizable Molecules on the Predictability of CoMFA
Kothandan, Gugan The Basic Science Institute Chosun University 2011 조선자연과학논문집 Vol.4 No.2
Effect of protonation and deprotonation of ionization compounds is an important application in Comparative molecular field analysis (CoMFA). There are enough information's were reported about different CoMFA applications such as Series design and selection of training set, Geometries and optimizations of molecules, Effect of partial atomic charges, bioactive conformations and alignment, Interaction energy fields, Effects of different grid spacing etc. However limited information's are available about the ionization of compounds. This study aimed at the critical review of about the effects of protonation of ionizable molecules and its impact on the predictability of CoMFA models. We also discussed about previous implications and the things needed to be considered to come for a final conclusion about its impact on CoMFA predictability.
Homology Modeling of GPR18 Receptor, an Orphan G-protein-coupled Receptor
Kothandan, Gugan,Cho, Seung Joo The Basic Science Institute Chosun University 2013 조선자연과학논문집 Vol.6 No.1
G-protein-coupled receptor (GPCR) superfamily is the largest known receptor family, characterized by seven transmembrane domains and considered to be an important drug target. In this study we focused on an orphan GPCR termed as GPR18. As there is no X-ray crystal structure has been reported for this receptor, we report on a homology model of GPR18. Template structure with high homology was used for modeling and ten models were developed. A model was selected and refined by energy minimization. The selected model was further validated using various parameters. Our results could be a starting point for further structure based drug design.
Kothandan, Gugan,Ganapathy, Jagadeesan The Basic Science Institute Chosun University 2014 조선자연과학논문집 Vol.7 No.2
Computer-aided drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. It is now proved to be effective in reducing costs and speeding up drug discovery. In this short review, we discussed on the importance of combining molecular docking and molecular dynamics simulation methodologies. We also reviewed the importance of protein flexibility, refinement of docked complexes using molecular dynamics and the use of free energy calculations for the calculation of accurate binding energies has been reviewed.
Kothandan, Gugan,Cho, Seung Joo The Basic Science Institute Chosun University 2012 조선자연과학논문집 Vol.5 No.4
Structure-based drug design possibly benefit from in silico methods that precisely predict the binding affinity of small molecules to target macromolecules. There are many limitations arise from the difficulty of predicting the binding affinity of a small molecule to a biological target with the current scoring functions. There is thus a strong interest in novel methodologies based on MD simulations that claim predictions of greater accuracy than current scoring functions, helpful for a regular use designed for drug discovery in the pharmaceutical industry. Herein, we report a short review on free energy calculations using MMPBSA method a useful method in structure based drug discovery.