Deciphering the mechanism behind the varied binding activities of COXIBs through Molecular Dynamic Simulations, MM-PBSA binding energy calculations and per-residue energy decomposition studies

Abstract

COX-2 is a well-known drug target in inflammatory disorders. COX-1/COX-2 selectivity of NSAIDs is crucial in assessing the gastrointestinal side effects associated with COX-1 inhibition. Celecoxib, rofecoxib, and valdecoxib are well-known specific COX-2 inhibiting drugs. Recently, polmacoxib, a COX-2/CA-II dual inhibitor has been approved by the Korean FDA. These COXIBs have similar structure with diverse activity range. Present study focuses on unraveling the mechanism behind the 10-fold difference in the activities of these sulfonamide-containing COXIBs. In order to obtain insights into their binding with COX-2 at molecular level, molecular dynamics simulations studies, and MM-PBSA approaches were employed. Further, per-residue decomposition of these energies led to the identification of crucial amino acids and interactions contributing to the differential binding of COXIBs. The results clearly indicated that Leu338, Ser339, Arg499, Ile503, Phe504, Val509, and Ser516 (Leu352, Ser353, Arg513, Ile517, Phe518, Val523, and Ser530 in PGHS-1 numbering) were imperative in determining the activity of these COXIBs. The binding energies and energy contribution of various residues were similar in all the three simulations. The results suggest that hydrogen bond interaction between the hydroxyl group of Ser516 and five-membered ring of diarylheterocycles augments the affinity in COXIBs. The SAR of the inhibitors studied and the per-residue energy decomposition values suggested the importance of Ser516. Additionally, the positive binding energy obtained with Arg106 explains the binding of COXIBs in hydrophobic channel deep in the COX-2 active site. The findings of the present work would aid in the development of potent COX-2 inhibitors.

Discrimination of Naturally-Occurring 2-Arylbenzofurans as Cyclooxygenase-2 Inhibitors: Insights into the Binding Mode and Enzymatic Inhibitory Activity

“…However, in comparison to the apoCOX-2, the binding with test ligands did not substantially modify the flexibility of these regions to maintain an overall steady state (RMSF differences > 0.2 nm), excepting the most-fluctuating residues around Arg106. Therefore, the COX-2 inhibition mode of compounds 11, 29, 42, and 49 might be interpreted through a complex stabilization, which is in agreement with the previously reported MD study for other known COX-2 inhibitors [34].…”

“…Regarding ligands, 42 exhibited similar binding energy to that of celecoxib (<−80 kJ/mol), which has the highest values among test ligands. Regarding residues, Arg106, Leu338, and Val509 were found to be those residues that contribute the most (<−8 kJ/mol) to the binding energy for the COX-2•celecoxib complex (as described previously [34]), whereas Arg106 and Arg499 were observed for COX-2 Val509 (<−6 kJ/mol) were the common residues that contributed to the binding energy for all test ligands. Such residues with higher binding energy contributions represented those contact points for electrostatic interactions, as described in molecular docking and Cα atom fluctuations.…”

Recent Developments and Applications of the MMPBSA Method

“…For immune disorders, studies on Janus kinases (Zhang W. et al, 2016 ; Wang J. L. et al, 2017 ), interleukin 10 cytokine (Ni et al, 2017 ), and receptor-related orphan receptor-gamma-t (Wang F. F. et al, 2015 ), were reported. For inflammatory disorders, targets such as COX-2 (Chaudhary and Aparoy, 2017 ), interleukin 6 (Verma R. et al, 2016 ), toll-like receptors (Shen et al, 2016 ), human leukocyte antigen (Kongkaew et al, 2015 ), chymase enzyme (Verma et al, 2017 ), tumor necrosis factor (Ivanisenko et al, 2014 ), and Nalp3 (Sahoo et al, 2014b ) were studied. For diabetes, analyses of targets included phosphorylase kinase (Begum et al, 2015 ), glycogen synthase kinase (Arfeen et al, 2015 ), protein kinase C beta II (Grewal and Sobhia, 2014 ), and dipeptidyl peptidase-4 enzyme (Gu et al, 2014 ; Sneha and Doss, 2016 ).…”

Deciphering the ‘Elixir of Life’: Dynamic Perspectives into the Allosteric Modulation of Mitochondrial ATP Synthase by J147, a Novel Drug in the Treatment of Alzheimer's Disease

“…This was done in order to considerably reduce or eliminate entropic effects on the binding energy of J147. [35][36][37] However, even though it is able to estimate the binding profiles of ligands to proteins, it is important to mention that MM/PBSA-based energy approximations are affected intrinsically by large uncertainties. [35][36][37]…”