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

Introduction
HIV Enzyme : Reverse transcriptase (RT) Protease integrase, dll Inhibitor AIDS

Replication

thiazolidinone derivatives

3D-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 QSAR
The 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 dose P = octanol - water partition coefficient

 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 Hhydration reduction potential lipophilicity parameter = log PX - log PH

Molecular Properties in QSAR

molecular weight dipole moment ()

Other 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 vdW surface area maximum + and charge molar refractivity hardness hydration energy Tafts steric parameter solvent accessible surface area

Molecular Properties in QSAR

CoMSI A

Metode ini dikenalkan oleh Klebe, dkk. Dengan kotak kisi yang sama seperti yang digunakan pada perhitungan CoMFA. Kelima sifat fisikokimia yang digunakan: sterik Elektrostatik Hidrofobik Donor ikatan hidrogen, dan Akseptor ikatan hidrogen

Result and Discussion

96 compounds in training set 17 compounds in test set

To develop CoMFA and CoMSIA models

To validate the developed model

PLS Statistic r SEE

2

CoMFA 0,861 0,429

CoMSIA 0,958 0,287

PLS statistics of CoMFA and CoMSIA test set compounds PLS Statistic r2 SEE CoMFA 0,861 0,429 CoMSIA 0,958 0,287

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, 6menurunkan aktivitas

CoMSIA
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 meningkat interaksi H.Bond dengan res. asam amino Cyan : HB donor : 4 : aktivitas meningkat Red : HB donor : 2, 6 : aktivitas menurun

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

Terima Kasih