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Predicting anti-HIV activity of 1,3,4-thiazolidinone derivatives: 3D-QSAR
approach
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Introduction
HIVHIV AIDSAIDS
Enzyme :Reverse transcriptase (RT)Proteaseintegrase, dll
Enzyme :Reverse transcriptase (RT)Proteaseintegrase, dll
ReplicationReplication
InhibitorInhibitor
thiazolidinone derivatives
thiazolidinone derivatives
3D-QSAR3D-QSAR
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Materials and Methods
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Rationale for QSAR Studies...
A quantitative structure-activity relationship (QSAR) correlates measurable or calculable physical or molecular properties to some specific biological activity in terms of an equation.Once a valid QSAR has been determined, it should be possible to predict the biological activity of related drug candidates before they are put through expensive and time-consuming biological testing.
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History of QSARThe first application of QSAR is attributed to Hansch (1969), who developed an equation that related biological activity to certain electronic characteristics and the hydrophobicity of a set of structures.
log (1/C) = k1log P - k2(log P)2 + k3 + k4
for: C = minimum effective doseP = octanol - water partition coefficient = Hammett substituent constantkx= constants derived from regression analysis
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Molecular Properties in QSAR• Many other molecular properties have been
incorporated into QSAR studies; some of these are measurable physical properties, such as:
•density
•pKa•ionization energy•boiling point•Hvaporization•refractive index
•density
•pKa•ionization energy•boiling point•Hvaporization•refractive index
•molecular weight•dipole moment ()•Hhydration•reduction potential•lipophilicity parameter = log PX - log PH
•molecular weight•dipole moment ()•Hhydration•reduction potential•lipophilicity parameter = log PX - log PH
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Molecular Properties in QSAROther molecular properties (descriptors) that have been incorporated into QSAR studies include calculated properties, such as:
•ovality •surface area, •molec. volume•HOMO energy •LUMO energy•polarizability•charges on individual atoms•molecular volume
•ovality •surface area, •molec. volume•HOMO energy •LUMO energy•polarizability•charges on individual atoms•molecular volume
•vdW surface area•maximum + and - charge•molar refractivity •hardness•hydration energy •Taft’s steric parameter•solvent accessible surface area
•vdW surface area•maximum + and - charge•molar refractivity •hardness•hydration energy •Taft’s steric parameter•solvent accessible surface area
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CoMSIA Metode ini dikenalkan oleh Klebe, dkk.
Dengan kotak kisi yang sama seperti yang digunakan pada perhitungan CoMFA.
Kelima sifat fisikokimia yang digunakan: sterikElektrostatikHidrofobikDonor ikatan hidrogen, danAkseptor ikatan hidrogen
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17 compounds in test set
96 compounds in training set
To develop CoMFA and CoMSIA
modelsTo validate the
developed model
Result and Discussion
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PLS Statistic CoMFA CoMSIAr2
SEE0,8610,429
0,9580,287
PLS Statistic CoMFA CoMSIAr2
SEE0,8610,429
0,9580,287
PLS statistics of CoMFA and CoMSIA test set compounds
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CoMFA• Red ; elektronegatif : 3’, 2”, 6” → aktivitas meningkat dengan
adanya gugus yg lebih elektronegatif & penarik elektron (CN, F, Br, Cl)
• Blue ; elektropositif : 4’ → aktivitas menurun dengan adanya gugus elektronegatif & penarik elektron.
• Yellow ; bulky : 2’, 4’, 2”, 3”, 6”→menurunkan aktivitas
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• White : gugus hidrofob : 3’, 2”, 6”-aktivitas anti-HIV meningkat →berinteraksi dengan residu asam amino dari HIV-1 reverse transcriptase.
• Yellow : gugus hidrofob : 4’, 3”, 4”Aktivitas biologi menurun
• Magenta : H.bond-Aceptor : 3’, 2”, 6”aktivitas meningkatinteraksi H.Bond dengan res. asam amino
• Cyan : HB donor : 4’ : aktivitas meningkat• Red : HB donor : 2”, 6” : aktivitas menurun
CoMSIA
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Kesimpulan
• Peta kontur dari CoMFA dan CoMSIA memberikan informasi yang berguna untuk desain senyawa baru turunan thiazolidinone dengan aktivitas anti-HIV yang lebih tinggi.
• Hasil ini membuktikan bahwa CoMFA dan CoMSIA merupakan metode yang terpercaya, dengan menunjukan bahwa substituen pada posisi 3’, 2”, 6” pada cincin aromatis thiazolidinone berperan penting dalam aktivitas anti-HIV, yang mana secara efisien dapat memandu dalam memodifikasi senyawa analog thiazolidinone.
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Terima Kasih