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

Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Preliminary study: Molecular Docking and 3D-QSAR Study on Pf ENR Inhibition by Triclosan Derivatives Department of Medicinal Chemistry University of Medicine and Pharmacy at Ho Chi Minh City The 7th PharmaIndochina Conference (14.01.2011) Dr Pharm Khac-Minh Thai thaikhacminh@gmail.com Dr Khac-Minh Thai Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam VOLUME 10 | DECEMBER 2011 | 887 GSK: RTS,S Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Introduction 3D QSAR models of triclosan derivatives on Pf ENR inhibition Docking study on Pf ENR Conclusions Contents Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam The global distribution of malaria, showing areas where Plasmodium falciparum resistance to the most commonly used antimalarial drugs, chloroquine and sulphadoxine-pyrimethamine (Nature 2004 - WHO 2008) - Killing 1–3 M people per year - Causing disease in 300–500 M people per 1 year Malaria Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam ( Nat Rev Drug Dis, 2010, 9(7), 511-2) Development of a malaria vaccine Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Selected antimalarial drugs in development ( Nat Rev Drug Dis, 2010, 9(7), 511-2) Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Targets for antimalarial chemotherapy ( Nat Rev Drug Dis, 2004, 3(6), 509-20) Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Pathway of fatty acid biosynthesis Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam P. falciparum Enoyl Acyl Carrier Protein Reductase Pf ENR Pf ENR Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam 1. Collection of Triclosan Database from Literature - the in vitro PfENR inhibition data IC 50 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 A B [...]... INFORMATIONat Ho Medicine and Pharmacy Chi Minh City, Vietnam -CH2-NH-CH2-R, -CH2-NH-C(O)-R Maximum R is 2 rings 2 Methyl, Ph with a halogen moiety A 5 A 2 B 4 B -C(O)-NH-R = Me or heterocylic containing nitrogen -NH-C(O)-R -NH-CH2-R –NH-SO2-R with R = Ar The positive effects on PfENR inhibition of triclosan derivatives from QSAR and docking results Dr Khac-Minh Thai Conclusions University of Medicine and. .. 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 Lead Optimisation For lead optimisation, we use conventional 2Dand 3D- QSAR methods as well as pharmacophore modeling and molecular holograms Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi... Pharmacy Docking studies on PfENR at Ho Chi Minh City, Vietnam Tyr277 Ala319 Ala217, Asn218, Ala219 pdb 3am3 P falciparum Enoyl Acyl Carrier Protein Reductase PfENR Dr Khac-Minh Thai University of Medicine and Pharmacy Docking studies on PfENR at Ho Chi Minh City, Vietnam BMC_05_35 IC50 = 0.11 μM Dr Khac-Minh Thai BMC_05_38 IC50 = 0.30 μM University of Medicine and Pharmacy Docking studies on PfENR at... 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 PfENR might useful to guide the design of new PfENR inhibitors which targeted in malaria Dr Khac-Minh Thai Drug Design - Pharmacoinformatics University of Medicine and Pharmacy... Chi Minh City, Vietnam 3D QSAR CoMSIA Model 3: Hydrophobic and H-bond acceptor (Observed versus calculated PfENR pIC50 plots) R2= 0.90 and SEE = 0.30 (49 training set compounds) r2= 0.55 and SEE = 0.23 (15 test set compounds) Dr Khac-Minh Thai BMC_2005_50 (pIC50 observed = 0.8539; pIC50 calculated = 1.1840) Hydrophobic: yellow mesh H-bond acceptor: blue mesh University of Medicine and Pharmacy at Ho Chi... Vietnam 3D QSAR CoMSIA Model 5: Hydrophobic, Steric and H-bond acceptor (Observed versus calculated PfENR pIC50 plots) R2= 0.92 and SEE = 0.27 (49 training set compounds) r2= 0.60 and SEE = 0.24 (15 test set compounds) Dr Khac-Minh Thai BMC_2005_50 (pIC50 observed = 0.8539; pIC50 calculated = 1.2320) Hydrophobic: yellow mesh Steric: green mesh H-bond acceptor: blue mesh University of Medicine and Pharmacy... Target Identification and Validation 12 11 3 7 4 10 1 5 6 9 8 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 Protein-Protein Interactions Hit Identification Selectivity profiling... Medicine and Pharmacy at Ho Chi Minh City, Vietnam 3D QSAR CoMSIA Model 2: Hydrophobic and Steric (Observed versus calculated PfENR pIC50 plots) R2= 0.94 and SEE = 0.24 (49 training set compounds) r2= 0.57 and SEE = 0.23 (15 test set compounds) Dr Khac-Minh Thai Triclosan (pIC50 observed = 1.1367; pIC50 calculated = 1.1920) Hydrophobic: yellow mesh Steric: green mesh University of Medicine and Pharmacy... Identification Selectivity profiling is performed on a on a systemic level and includes modeling of proteinprotein interactions Hit identification comprises use of artificial neural networks, autocorrelation vectors and VolSurf descriptors Emerging Focus Pharmacoinformatics Virtual Screening Structure based Design Virtual screening of large compound libraries is performed on basis of our recently developed SIBAR-technology,... 4 0.500 0.269 0.918 0.602 5 4 0.544 0.269 0.918 0.602 University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam 3D QSAR CoMSIA Model 1: Hydrophobic Triclosan (pIC50 observed = 1.1367; pIC50 calculated = 1.1470) (Observed plots) versus calculated PfENR pIC50 R2= 0.92 and SEE = 0.28 (49 training set compounds) r2= 0.64 and SEE = 0.23 (15 test set compounds) Dr Khac-Minh Thai Hydrophobic: yellow . Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Preliminary study: Molecular Docking and 3D-QSAR Study on Pf ENR Inhibition by Triclosan Derivatives Department of Medicinal. Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Introduction 3D QSAR models of triclosan derivatives on Pf ENR inhibition Docking study on Pf ENR Conclusions Contents Dr Khac-Minh. Docking studies on Pf ENR Dr Khac-Minh Thai University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam DESIGN INFORMATION The positive effects on Pf ENR inhibition of triclosan derivatives