Virtual screening for novel COX-2 inhibitors using the ZINC database

Abstract

Cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid and releases metabolites that are used to induce pain and inflammation. COX-2 selective inhibitors such as celecoxib, rofecoxib and valdecoxib are currently used to reduce inflammatory response. However, they lack anti-thrombotic activity and hence lead to cardiovascular and renal liabilities apart from gastrointestinal irritation. Therefore, there is still a need to develop more potent COX-2 inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains 4.6 million small molecule compounds) using the eHiTS (electronic High Throughput Screening) software tool against the COX-2 protein. The strategy employed can be conveniently split into two categories, viz. screening and docking, respectively. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 6COX bound ligand SC-558. The analysis resulted in 1042 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified two molecules ZINC00663976 (eHITS score of -7.135 kcal/mol) and ZINC02062094 (eHITS score of -7.242 kcal/mol) from the ZINC database. Their energy scores are better than the 6COX bound co-crystallized ligand SC-558 with an eHiTS score of -6.559 kcal/mol. Both the ligands were docked within the binding pocket forming interactions with Leu352, Phe518, Met522, Val523, Ala527 and Ser353. Visual inspection suggested similar orientation and binding mode for ZINC02062094 with SC-558 ligand. The NH group of the ligand formed hydrogen bond interactions with the backbone NH of Ala527.

Construction and Optimization of Structure-Based Virtual Screening Protocols to Identify Cyclooxygenase-1 Inhibitors Using Open Babel, Spores and Plants

“…The availability of the directory of useful decoys (DUD) which has provided libraries to benchmark the SBVSs for both COX-1 and COX-2 are very beneficial to retrospectively validated the developed SBVS protocols [7]. Some efforts to develop SBVS tools to identify COX-2 inhibitors have been performed and resulted in SBVS protocols with good quality [7][8][9][10]. The availability of some new COX-2 crystal structures has also opened more opportunities to increase the quality of the available SBVS protocols in identifying COX-2 inhibitors [11].…”

Identification of small molecule binding pocket for inhibition of Crimean–Congo hemorrhagic fever virus OTU protease

“…Computational chemistry for in silico screening is now an established platform for identification of lead compounds in the drug discovery process (Yang et al, 2007;Sudha et al, 2008;Chang et al, 2010;Wassman et al, 2013). This approach utilizes the prediction of binding poses and affinities of each docked compound to the crystal structure of a target protein.…”

Molecular docking study of active phytocompounds from the methanolic leaf extract of <i>vitex negundo</i> against cyclooxygenase-2

“…COX-2 is an oxidoreductase enzyme playing a role in prostaglandin biosynthesis and inflammatory responses. The COX-2 enzyme binds to arachidonic acid which causes pain and inflammation (Sudha et al, 2008). COX-2 is one of the well-known targets for the antiinflammatory therapy.…”