International Journal of Computational Biology and Drug Design (10 papers in press)
Data Acquisition and Electrical Instrumentation Engineering Modelling for Intelligent Learning and Recognition
by Jun Qin, Yuhao Jiang
Development of interactive computer learning program for genetics and molecular biology applications
by Xiaoli Yang, Bin Chen, Yifan Cai, Charles Tseng
Comparative conformational variation and flexibility analysis of binding site D-loop and its importance in designing of potential tankyrases inhibitors
by Rakesh D. Nimbalkar, Sujit R. Tangadpalliwar, Prabha Garg
Abstract: The principle point of this study is to know the dynamics of D-loop affecting the inhibitory action of tankyrase inhibitors. The knowledge of D-loop conformational variations, flexibility analysis, and its significance in the binding of tankyrase inhibitors (TNKSIs) has not been explored earlier. This study at first focused on observing the conformational changes of D-loop in tankyrases crystal structures. These conformational changes were observed by overlapping of D-loop residues for their open inward and open outward conformation as well as to describe the movement of D-loop towards the neighboring loop (N-loop) or not. Comparative analysis of D-loop of TNKS1 and TNKS2 shows that D-loop of TNKS2 has its conformation more towards the neighboring N-loop. Flexibility analyses of both the isoforms of TNKSs have indicated the most extreme movement of D-loop in the presence of adenosine and nicotinamide site inhibitors. The presence of dual site inhibitor doesn't influence the movement of D-loop significantly. To achieve this, relative residue fluctuation profile examination of undocked and docked complexes were performed. Further, MM/GBSA free energy calculations were used to expose the more prominent binding strength of strong inhibitors and selectivity compared to other respective site inhibitors. Molecular dynamics simulation search revealed that RMSF profile of D-loop of TNKSs affects the binding potential of inhibitors. Thus conformational changes in the D-loop affected by inhibitors can be used to screen the potent tankyrase inhibitors (TNKSIs). The molecular docking, D-loop flexibility analysis, molecular dynamics and MM/GBSA binding energy calculations were carried out.
Keywords: Tankyrase-1; TNKS1; Tankyrase-2; TNKS2; Prime MM/GBSA; molecular docking; Molecular dynamic simulations; D-loop; residue fluctuation.
Interaction of Curcumin with Different Target Proteins of Alzheimers Disease: Docking and MD Simulation Studies
by Shraddha Sriraman, Nanda Gopal Saha, Sujata Roy
Abstract: Curcumin, commonly called turmeric, is a polyphenol derived from the rhizome of the plant, Curcuma longa. Curcumin has been extensively used in the treatment of various medical conditions, including arthritis, cystic fibrosis, and cancer and so on. In addition, curcumin also has a potential role in the prevention and treatment of Alzheimer's disease (AD). Although the effect of curcumin with regards to AD has been studied experimentally, the molecular mechanism is still unknown. Many targets of AD have been identified. In this analysis, the interactions of curcumin with eight different targets of AD have been studied, in order to locate the binding site of curcumin. Based on docking energy, three potential targets such as acetylcholinesterase, cholinesterase and inducible nitric oxide synthase have been selected. Then, MD simulation was performed for those three docked structures. It was found that acetylcholinesterase was the best target of curcumin. Existing experimental results support this finding. The dynamics of interaction at the atomic level was studied to understand the main chemical property of curcumin that can be exploited in treating AD.
Keywords: Alzheimer's disease; Curcumin; Acetylcholinesterase; Molecular Docking and Molecular Dynamics.
An Improved Convex and Concave Index for Revealing the Exposure Degree of Atoms in Protein 3D Structure
by Xiao Wang, Jian Zhao, Yujiao Yan, Jingye Qian, Ping Han, Xiaofeng Song
Abstract: Geometry property of protein surface contributes largely to the protein function in the cells, descriptors of measuring the convexity and concavity of protein surfaces can help to understand the protein function. Motivated by CX algorithm, we developed an improved surface structural parameter named convex-and-concave index (CCI) to describe geometric properties of protein surface. The proposed CCI eliminates the defect of coarse computing for the overlap volume of two adjacent atom spheres in CX algorithm, by dividing the probe sphere into many cubic lattices and labelling the cubic lattices inside the atoms or not respectively. The results indicated that the CCI algorithm improved the accuracy of CX, and not increased the computing complexity. The proposed CCI is a fast and simple method that can accurately describe the exposure degree of atoms in protein and reveal protein functional sites, such as active sites and ubiquitination site.
Keywords: structural parameter; convex-and-concave index; degree of exposure; protein surface; active site; ubiquitination site.
The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery.
by Clifford Fong
Abstract: A multiparameter model of the diffusion, antiproliferative assays IC50 and aerobic and hypoxic clonogenic assays for a wide range of neutral and radical anion forms of tirapazamine (TPZ) analogues has found that: (a) extravascular diffusion is governed by the desolvation, lipophilicity, dipole moment and molecular volume, similar to passive and facilitated permeation through the blood brain barrier and other cellular membranes, (b) hypoxic assay properties of the TPZ analogues show dependencies on the electron affinity, as well as lipophilicity and dipole moment and desolvation, similar to other biological processes involving permeation of cellular membranes, including nuclear membranes, (c) aerobic properties are dependent on the almost exclusively on the electron affinity, consistent with electron transfer involving free radicals being dominant with little or no drug permeation of membranes, and most likely occurring in the extracellular matrix. Application of the model to the DNA binding equilibrium constants of TPZ analogues with acridine or acridine-like moieties show that ligand water desolvation and lipophilicity are the dominant processes governing the DNA intercalation of TPZ analogues. This conclusion is consistent with DFT modelling of the complexes formed by TPZ analogues with neutral and N-protonated acridine moieties which intercalate with the guanine DNA nucleobases. A quantum mechanical study has shown that TPZ can form stable complexes with cucurbituril as a precursor to proof of principle of improved TPZ delivery to tumours.
Keywords: Tirapazamine analogues; intra-tumoural diffusion; anti-cancer; hypoxia; cytotoxicity; DNA binding; cucurbiturils; quantum mechanics.
Structural analysis of protein translocase subunit SecY from Mycobacterium tuberculosis H37Rv: a potential target for anti-tuberculosis drug discovery
by Tilahun Melak Sitote, Sunita Gakkhar
Abstract: Identification of noble drug targets is a very important step in the development of anti-mycobacterial drugs to counter the problem of drug-resistance. The availability of structural information of a specified drug target is one of the druggablity criteria. However, many proteins do not have experimentally solved structure in spite of the efforts of structural genomics projects. In this study, structural analysis on a selected potential drug target of Mycobacterium tuberculosis H37Rv has been carried out. Protein translocase subunit SecY (Rv0732) has been selected since it is a highly ranked potential drug target without solved three-dimensional structure. In silco structural analysis has been carried out to get descriptive three-dimensional structure. The models were generated using Crystal Structure of Secye Translocon from Thermus thermophilus with a Fab Fragment (2ZJS_Y) as a template. The active site has been identified for protein-inhibitor binding.
Keywords: Active site; Drug-resistance tuberculosis; Homology modeling.
Identification of dual target anti-inflammatory inhibitors using merged structure based pharmacophore modelling and docking approach
by Manikandan Selvaraj, Muhd Hanis MD Idris, Siti Norhidayu Mohd Amin, Mohd Zaki Salleh, Teh Lay Kek
Abstract: Merged structure-based pharmacophore modelling followed by 3-D database search and molecular docking were the sequential protocol applied in order to identify selective novel COX-2 and PDE4D as dual target anti-inflammatory inhibitors. Utilization of the key interaction features of crystal structures of COX-2 (pdb: 1CX2) and PDE4D (pdb: N0YN) was exploited as critical component in the selection of dual target inhibitors. Through this approach, nine chalcone and flavones scaffold like compounds were selected as putative dual target anti-inflammatory inhibitors from Asinex database. In general understanding such approach could provide valuable insights into discovery of novel anti-inflammatory inhibitors as therapeutic agents.
Keywords: Cyclooxygenase; phosphodiesterase; dual target; merged pharmacophore; docking.
Special Issue on: ICIBM 2016 Recent Advances in Computational Systems Biology and Bioinformatics
A Flexible Approach to Reconstruct the Genomic Spatial Structure by the Genetic Algorithm
by Yan Zhang, William Hoskins, Ruofan Xia, Xiya Xia, Jim W. Zheng, Jijun Tang
Abstract: The 3D structures of the chromosomes play fundamental roles in essential cellular functions, e.g. gene regulation, gene expression, evolution. HiC technique provides the interaction density between loci on chromosomes.\r\nSeveral approaches have been developed to reconstruct the 3D model of the chromosomes from HiC data. However, all of the approaches are based on a particular mathematical model and lack of flexibility for new development.\r\nWe introduce a novel approach using the genetic algorithm. Our approach is\r\nflexible to accept any mathematical models to build a 3D chromosomal structure.\r\nAlso, our approach outperforms current techniques in accuracy
Keywords: : Genome; Spatial Structure; Genetic Algorithm; HiC.
Signal Translational Efficiency between mRNA Expression and Antibody-based Protein Expression for Breast Cancer and its Subtypes from Cell lines to Tissue
by Aida Yazdanparast, Lang Li, Milan Radovich, Lijun Cheng
Abstract: Background: Although gene transcripts and protein expression have been utilized to classify breast cancer subtypes, it is not clear whether the observed measurement of gene transcript abundance can predict its protein expression. Herein, we attempt to address gene transcript/protein associations using publically-available data on breast cancer tumor tissues and cell lines. Method: Correlation analysis between mRNAs and Reverse-phase protein arrays (RPPA) among 421 primary breast tumors and 33 breast cancer cell lines was conducted. Highly concordant proteins/genes were further analyzed in different breast cancer subtypes. Results: The overall accordance of mRNA/RPPA correlation between cell lines and primary tissue is R2=0.71. Since most of these genes are well known drug targets, highly concordant gene/RPPA associations not only confirm that these gene transcripts can serve as biomarkers for their protein products in drug target selection, but also imply that breast cancer cell lines can serve as good models for primary breast cancer tumors.
Keywords: Breast cancer; Reverse-phase protein array; mRNA; Cell lines; Protein abundance.