Investigation of fragment based quantitative regression on a series of substituted chromen-2-one derivatives as FXa inhibitors

Abstract

Factor Xa (FXa), a trypsin-like serine protease, is wellestablished

target for the development of the anticoagulants.

Number of molecules were reported as Factor Xa inhibitors

but most of them have pharmacokinetic issues. In this present

communication, we report development and validation of

the group based quantitative structure activity relationship

(GQSAR) studies on 48 chromen-2-one derivatives as effective

inhibitors of FXa. All the molecules were fragmented into eleven

functional fragments (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10

and R11). All the developed GQSAR models were generated

using multiple linear regression analysis (MLR). The generated

GQSAR models were selected on the basis of statistical data that

models having r2 should be above 0.6 were used to check the

external predictivity while the significance of the model was

decided on the basis of F value. Developed GQSAR models

reveled presence of lipophilic groups on fragment R6 will

diminish the bio-activity while at R2 it will lead to increase

in bioactivity of molecules. Additionally, minimum number

of rotatable bonds at fragments R1 was fruitful for better FXa

inhibition activity. The results of GQSAR models may lead to

better understanding of design and development of novel FXa

inhibitors.

Keywords

• FXa,Vlife MDS,Anticoagulant,Quantitative Structure Activity Relationship,GQSAR,Slogp

Fxa inhibitörü etkili sübstitüe kromen-2-on bileşiklerinin fragment temelli kantitatif regresyon özelliklerinin incelenmesi

Abstract

Faktör Xa (FXa), tripsin-benzeri bir serin proteaz olup

antikoagülan etkili bileşiklerin tasarlanmasında temel alınan

önemli bir hedeftir. Literatürde, Faktör Xa inhibitörü olduğu

bildirilen birçok bileşiğin farmakokinetik açıdan sorunlu

olduğu bildirilmektedir. Bu çalışmada, FXa’yı önemli ölçüde

inhibe eden 48 kromen-2-on türevinin grup temelli kantitatif

yapı etki ilişkisi (GQSAR) üzerinde çalışılmış ve elde edilen

bulgular doğrulanmıştır. Bütün bileşikler onbir fonksiyonel

fragmente (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 ve R11)

ayrılarak incelenmiştir. Geliştirilen tüm GQSAR modelleri çoklu

lineer regresyon analizi (MLR) kullanılarak oluşturulmuştur.

Geliştirilen GQSAR modellerinden r2 değerleri 0.6’nın üzerinde

olanlar istatistiksel yöntemler doğrultusunda seçilmiş ve dış

tahmine dayalı analiz yönteminin sağlamasını yapmak amacıyla

kullanılmış, oluşturulan modelin anlamlılığı F değeri dikkate

alınarak tanımlanmıştır. Geliştirilen GQSAR modelleri; lipofilik

grupların fragment R6 üzerindeki varlığının biyoaktiviteyi

azalttığını, fragment R2 üzerinde bulunmaları durumunda ise

biyoaktivitenin arttığını göstermiştir. Buna ek olarak, fragment

R1’de minimum sayıda dönebilen bağ olması durumunun FXa

inhibisyonunu arttırdığı tespit edilmiştir. GQSAR modellerinin

incelenmesi ile elde edilen sonuçların yeni FXa inhibitörlerinin

tasarımı ve geliştirilmesi için yararlı olduğu düşünülmektedir.

Keywords

• FXa,Vlife MDS,Antikoagülan,Kantitatif Yapı Etki İlişkisi,GQSAR,Slogp

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