Molecular docking and 3d QSAR study on PfENR inhibition by triclosan derivatives

at Ho Chi Minh City, Vietnam Preliminary study: Molecular Docking and 3D-QSAR Study on Department of Medicinal Chemistry University of Medicine and Pharmacy at Ho Chi Minh City 14.01.2

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at Ho Chi Minh City, Vietnam

Preliminary study:

Molecular Docking and 3D-QSAR Study on

Department of Medicinal Chemistry University of Medicine and Pharmacy at Ho Chi Minh City

(14.01.2011)

Dr Pharm Khac-Minh Thai

thaikhacminh@gmail.com

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University of Medicine and Pharmacy

VOLUME 10 | DECEMBER 2011 | 887

GSK: RTS,S

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The global distribution of malaria, showing areas where

- Killing 1–3 M people per year

- Causing disease in 300–500 M people per 1 year

Malaria

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(Nat Rev Drug Dis, 2010, 9(7), 511-2)

Development of a malaria vaccine

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at Ho Chi Minh City, Vietnam Selected antimalarial drugs in development

(Nat Rev Drug Dis, 2010, 9(7), 511-2)

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at Ho Chi Minh City, Vietnam Targets for antimalarial chemotherapy

(Nat Rev Drug Dis, 2004, 3(6), 509-20)

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Pathway of fatty acid biosynthesis

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Pf ENR

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1 Collection of Triclosan Database

from Literature

- the in vitro PfENR inhibition data IC50 value (74/83)

2 Generation 3D- Structure of triclosan Database

EM/MD

3 3D Structures Alignment

4 Calculation of 3D Descriptors CoMFA/CoMSIA

6 PLS Analysis on Training Set

- r 2, , SEE

- Crossvalidated q 2 , SEE (LOO)

7 Validation QSAR Model

on test sets and external sets

5 Definition of Training & Test Sets

Training set: 59 Test set: 15

Sybyl/Tripos

3D QSAR

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Models Descriptor field Column filter Optimum number of

r2

(test set)

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3D QSAR CoMSIA Model 1:

Hydrophobic

(Observed versus calculated Pf ENR pIC50

plots)

R 2 = 0.92 and SEE = 0.28 (49 training set compounds)

r 2 = 0.64 and SEE = 0.23 (15 test set compounds)

Triclosan

(pIC50 observed = 1.1367;

pIC50 calculated = 1.1470)

JBC_2007_20

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Hydrophobic and Steric

(Observed versus calculated Pf ENR pIC50 plots)

Triclosan

Hydrophobic: yellow mesh

Steric: green mesh

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Hydrophobic and H-bond acceptor

BMC_2005_50

H-bond acceptor: blue mesh

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Hydrophobic, Steric and H-bond acceptor

BMC_2005_50

Steric: green mesh

H-bond acceptor: blue mesh

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Docking studies on Pf ENR

pdb 3am3

Ala217, Asn218, Ala219 Tyr277

Ala319

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BMC_05_35

IC50 = 0.11 μM IC BMC_05_3850 = 0.30 μM Docking studies on Pf ENR

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Docking studies on Pf ENR

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at Ho Chi Minh City, Vietnam DESIGN INFORMATION

The positive effects on Pf ENR inhibition of triclosan

derivatives from QSAR and docking results

2

Methyl,

Ph with a halogen moiety

Maximum R is 2 rings

-C(O)-NH-R = Me or heterocylic containing nitrogen

-NH-C(O)-R -NH-CH2-R –NH-SO2-R with R = Ar

5

2

4

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at Ho Chi Minh City, Vietnam Conclusions

Analogue Design as a Means of Discovering New Drugs:

(i) New Uses for Old Drugs

(ii)The PASS Program (Prediction of Activity Spectra for Substances)

(iii) New Leads from Old Drugs: The SOSA Approach

(Selective Optimization of Side Activities)

(Camille G Wermuth)

The information obtained from 3D QSAR and docking studies on Pf ENR might useful to guide the design of new Pf ENR inhibitors which targeted in malaria

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Target Identification and Validation

For human ABC-transporter, the dataset of Gottesman is the main source for substrate patterns For infectious deseases targets are identified via screening of bacterial and fungal genomes for ABC-pumps

Considerations on drugability includes analysis of the regulatory networks

Hit Identification

Hit identification comprises use of artificial neural networks, autocorrelation vectors and VolSurf descriptors

Virtual Screening

Virtual screening of large compound libraries is performed on basis of our recently developed SIBAR-technology, which utilises similarity based algorithms.

Lead Optimisation

For lead optimisation, we use conventional and 3D-QSAR methods as well as pharmacophore modeling and molecular holograms

2D-Structure based Design

Up to now no high resolution structure of a human ABC-transporter is available Photoaffinity labeling and protein homology modeling pave the way for structure-based design and molecular basis of function

Protein-Protein Interactions

Selectivity profiling is performed on a on a systemic level and includes modeling of protein- protein interactions

Emerging Focus Pharmacoinformatics

11

12 7

10 9

Drug Design - Pharmacoinformatics

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FUND:

The Vietnam's National Foundation for Science and Technology Development - NAFOSTED (Grant # 104.01.21.09 to Khac-Minh Thai)

Prof Dr Tran Thanh Dao

Dr Huynh Thi Ngoc Phuong

Nguyen Dac Chi

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