2d-classification and 3d-qsar research of benzimidazole-based respiratory syncytial virus fusion...

2D-classification and 3D-QSAR research of benzimidazole-based respiratory syncytial

virus fusion inhibitorsDingjue Ji, Yaojin Sun

Department of Bioinformatics and Biostatistics, School of Life Science, Shanghai Jiaotong University

800 Dongchuan RD, Shanghai, China

Outline

•Introduction

•Methods

•Results

•Q&A

Introduction“A virus is a small infectious agent that replicates only inside the living cells of other organisms.”

•Human respiratory syncytial virus

•Isolated from chimpanzee

•respiratory health threat to newborn infants and young children.

•elderly and high-risk adults with underlying chronic pulmonary disease and the severely immunocompromised

What is RSV?

Impact of RSV

•132,000 to 172,000 hospitalizations among children ,5 years of age

•100,000 to 126,000 hospitalizations among children ,1 year of age

•1.5 million outpatient visits among children ,5 years of age

Therapy

•Palivizumab

•Medi-534

•Ribavirin

•CathelicidinMore!

How we start

•CoMFA

•CoMSIA

•Molecular dynamics simulationCombination!

Methods“Chemical biology is a scientific discipline spanning the fields of chemistry, biology, and physics. It involves the application of chemical techniques, tools, and analyses, and often compounds produced through synthetic chemistry, to the study and manipulation of biological systems.”

Data sets

Molecular Modeling and Alignment

•3D structure built by SYBYL modeling program

•Emphasis on the common structure

•BMS-433771 examined in vivo

•benzimidazole, benzimidazolinone, or both

Two-dimensional representation

Molecular Docking

•1G2C

•Well-defined binding site near Y198

•Autodock4.0/Vina package

•For QSAR model and initial structure of MD

CoMFA Models

•Comparative Molecular Field Analysis

•Molecules aligned within a lattice which is rife with arranged probe

•Coulomb potential and Lennard-Jones potential

•Partial least squares

•3:1

CoMSIA Models

•Comparative Molecular Similarity Indices Analysis

•Five force field

•Gaussian-type potential

Results“Bioinformatics is an interdisciplinary field that develops methods and software tools for understanding biological data.”

QSAR models

QSAR models

QSAR models

QSAR models

QSAR models

QSAR models

Preprocessing

Categorical x

[-1,1] with abundance over 80% x

Correlation over 80% x

Internal coding of perl

Classification

potent(PEC50>7) and weak(PEC50<7)BP neural network

SVM

Random Forest

Coding of R

Preview of BP results

pre Potent Weak Potent 147 33 Weak 7 104

pre2 Potent Weak Potent 25 23 Weak 9 22

Preview of RF resultspre Potent Weak Potent 154 0 Weak 0 137

pre2 Potent Weak Potent 26 15 Weak 8 30

Preview of SVM results

pre Potent Weak Potent 138 26 Weak 16 111

pre2 Potent Weak Potent 26 16 Weak 8 29

Further Works

Basic statistics of evaluation

Analyze relation between QSAR model and receptor

Try to reveal binding mechanism and give advice on modification

Q&A“Plato is dear to me, but dearer still is truth.”