Computational Drug Discovery and Design

Binding free energy calculation of both ligand–protein complexes

were carried out using MM-GBSA, which gives binding free energy

estimation of
80.063 kcal/mol for C_773 and
73.791 kcal/

mol for C_997. Binding efficiency of predicted drug molecules

were also compared with already available anti-inflammatory drug

molecule (Bextra, Celebrex, and Vioxx) using same protocol

(Table2). It was found that both predicted molecules show similar

binding affinity as those of already available drug molecules with

high specificity toward COX-2 enzyme.

Docking and simulation studies showed that the predicted

compounds were showing good affinity and selectivity toward

COX-2. This does not imply that predicted compounds are poten-

tial lead molecules until they satisfy all physicochemical and phar-

macokinetic properties of drug-like molecule. ADMET properties

of C_773 and C_997 were predicted using Qikprop tool of Schro-

dinger suite and webserver admetSAR. Both molecules passed all

five criteria of Lipinski’s rule and their solvent accessible surface

area (SASA) was within reference range suggested by QikProp.

Blood–brain barrier (BBB) permeability was also predicted negative

ensuring its administration safe for brain. Knowing that both pre-

dicted molecules satisfy all drug-likeliness properties, synthetic

accessibility of these compounds was also checked in order to rule

out the risk of failure at the time of chemical synthesis. “Synthetic

Accessibility” program of myPresto (Medicinally Yielding PRotein

Table 2
Docking scores of predicted compounds docked against COX-1 and COX-2 and three already
available drug molecules docked against COX-2

Ligand

Docking

score for

COX-2

Docking

score for

COX-1

Hydrogen bonds

interactions formed with

COX-2 residues after MDS

Hydrophobic interactions formed

with COX-2 residues after MDS

C_773 
10.298 
3.806 Asn 361and Phe 515 Phe 195, Gly 213, Val 214, Val

330, Val 335, Ile 363, Phe 367, Leu

370, Trp 373, Met 508, Val 509, Gly

512, Ser 516, Gly 519, Leu 520, Asn

523

C_997 
8.688 
3.435 Asn 361 and Met 508 Phe 195, His 212, Gly 213, Ile

363, Phe 367, Leu 370, Tyr

371, Phe 504, Gly 512, Ala 513, Ser

516, Gly 519, Leu 520, Asn 523

Valdecoxib 
9.458 – – –

Celecoxib 
9.878 – – –

Rofecoxib 
9.767 – – –

Interactions formed by predicted molecules with COX-2 protein residues after molecular dynamic simulations are also
listed

136 Shashank P. Katiyar et al.