Predicting anti-HIV activity of 1,3,4-thiazolidinone derivatives: 3D-QSAR

approach

Introduction

HIVHIV AIDSAIDS

Enzyme :Reverse transcriptase (RT)Proteaseintegrase, dll

Enzyme :Reverse transcriptase (RT)Proteaseintegrase, dll

ReplicationReplication

InhibitorInhibitor

thiazolidinone derivatives

thiazolidinone derivatives

3D-QSAR3D-QSAR

Materials and Methods

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.

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

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

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

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

17 compounds in test set

96 compounds in training set

To develop CoMFA and CoMSIA

modelsTo validate the

developed model

Result and Discussion

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

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

• 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

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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