Development of QSAR model for immunomodulatory activity of natural coumarinolignoids

Abstract

Immunomodulation is the process of alteration in immune response due to foreign intrusion of molecules inside the body. Along with the available drugs, a large number of herbal drugs are promoted in traditional Indian treatments, for their immunomodulating activity. Natural coumarinolignoids isolated from the seeds of Cleome viscose have been recognized as having hepatoprotective action and have recently been tested preclinically for their immunomodulatory activity affecting both cell-mediated and humoral immune response. To explore the immunomodulatory compound from derivatives of coumarinolignoids, a quantitative structure activity relationship (QSAR) and molecular docking studies were performed. Theoretical results are in accord with the in vivo experimental data studied on Swiss albino mice. Immunostimulatory activity was predicted through QSAR model, developed by forward feed multiple linear regression method with leave-one-out approach. Relationship correlating measure of QSAR model was 99% (R(2) = 0.99) and predictive accuracy was 96% (RCV(2) = 0.96). QSAR studies indicate that dipole moment, steric energy, amide group count, lambda max (UV-visible), and molar refractivity correlates well with biological activity, while decrease in dipole moment, steric energy, and molar refractivity has negative correlation. Docking studies also showed strong binding affinity to immunomodulatory receptors.

Keywords: QSAR; coumarinolignoids; docking; immunomodulation; regression model.

Figure 1

Molecular differences in different coumarinolignoids derivatives. Prototype 1 and 2 are showing fusion of coumarin moiety with the phenylpropanoid unit (C6C3). Bold face indicates active and isolated compounds. Asterisk indicates that compounds were isolated as racemic mixture.

Figure 2

Molecular structure of the purified active natural coumarinolignoids isoforms 1a (Cleomiscosin-A), 1f (Cleomiscosin-C), and 2a (Cleomiscosin-B) isolated from the seeds of C. viscosa.

Figure 3

Superimposition of most favorable conformations of compounds 1a, 2a, 1f, and diclofenac docked into binding site of COX-2 receptor showing common pharmacophore ring structure.

Figure 4

Binding affinity of cleomiscosin A, B, and C against toll-like receptors (TLRs). Docking scores (kcal/mol) in negative are acceptable.

Figure 5

Binding affinity of cleomiscosin A, B, and C with various cluster of differentiation molecules (CD molecules) and T-cell receptor proteins. Negative docking scores (kcal/mol) are acceptable.

Figure 6

Binding affinity of cleomiscosin A, B, and C with various immune reaction cascade proteins and inducible nitric oxide synthase (iNOS) protein. Negative docking scores (kcal/mol) are acceptable.