Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

Abstract

The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

“…After the application of the reduction and selection filters of the 2000 compounds, they were submitted to similarity to Tanimoto to find out which ones are closer to the characteristics of the pivot molecule used in the process (Rofecoxib). The fifty eight (58) molecules were obtained with a Tanimoto index greater than 0.35 (see Table 6), which is a value that is considered reasonable for the application of toxicological and pharmacological prediction studies in silico, with three promising molecules being selected during these tests as reported below, subsequently applying the molecular coupling and molecular dynamics tests [18]. Table 7 shows the best results of the toxicological tests applied to the three inhibitors selected through the Tanimoto index and tests performed through the online server PreADMET (https: //preadmet.bmdrc.kr/adme/) in order to screen those who present better absorption, distribution, and metabolism values besides limiting the possibilities of mutagenicity through toxicological tests.…”

Mitigating antimicrobial resistance with aspirin (acetylsalicylic acid) and paracetamol (acetaminophen): Conversion of doxycycline and minocycline resistant bacteria into sensitive in presence of aspirin and paracetamol

“…In the past numerous molecules of non-antibiotic nature earlier acknowledged as anthelmintics, anticancer drugs, antipsychotics, antidepressant drugs, antiplatelets and NSAIDs have been evaluated for their antimicrobial potential (3, 4). Some of the cyclooxygenase inhibitory anti-inflammatory and antipyretic drugs (5) such as acetaminophen (paracetamol), acetylsalicylic acid (aspirin), diclofenac and ibuprofen, flurbiprofen and similar non-steroidal anti-inflammatory drugs (NSAIDs) almost consistently used along with antimicrobial therapy have also been explored for their antimicrobial potential. The most commonly used on-counter NSAIDs (aspirin and paracetamol) are known less for their antibacterial activity in acceptable therapeutic dosages but are reported to enhance the performance of antibiotics either through their synergistic antibacterial action with antibiotics (6–9) or through reducing adherence, production of biofilm, and other virulence factors, and altering antibiotic susceptibility of pathogens (4, 5).…”

Extraction Yield, Chemical Composition, Preliminary Toxicity of Bignonia nocturna (Bignoniaceae) Essential Oil and in Silico Evaluation of the Interaction

“…In silico molecular docking simulations have been applied to investigate the interaction of bioactive compounds of natural origin with proteins of pharmacological interest [36,37] . We used this technique to investigate whether benzaldehyde, a major compound in essential oil from Bignonia nocturna , is capable of interacting with the acetylcholinesterase (AChE) protein.…”