Computational exploration of novel ketoprofen derivatives: Molecular dynamics simulations and MM-PBSA calculations for COX-2 inhibition as promising anti-inflammatory drugs.

Computer-aided drug design is widely employed to identify novel compounds for therapeutic applications. Ketoprofen (KTP), a commonly used and marketed nonsteroidal anti-inflammatory drug (NSAID), is effective in treating pain, fever, inflammation, and some cancers. In this research, we explored the behavior of six analogues designed by structurally modifying the KTP molecule. Specifically, KTP-A and KTP-B contain a -CN group at the ortho position, KTP-C and KTP-D have a -CN group at the meta position, and KTP-E and KTP-F feature a -CF3 group at the meta position. To assess these analogues, we conducted molecular dynamics simulations (MD) to study their inhibitory effects on human cyclooxygenase 2 (COX-2), providing detailed insights into the structure and dynamics of the protein both with and without ligands. MD simulation, enhanced by technological advances, has proven to be a powerful tool for new drug discovery. We further quantified the binding affinity of these drug molecules toward COX-2 using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The dynamic properties were evaluated through analyses of root mean square deviations (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), covariance matrix, principal component analysis (PCA), and Gibbs free energy landscapes (FEL). Ultimately, this study confirms that the six KTP derivatives are promising candidates for the treatment of inflammation, with KTP-B standing out as particularly effective.

In silico design based on quantum chemical, molecular docking studies and ADMET predictions of ciprofloxacin derivatives as novel potential antibacterial and antimycrobacterium agents.

Drug designing and development is an important area of research for pharmaceutical companies and chemical scientists. In this paper, we report the prediction of new ciprofloxacin derivatives by quantum chemical, molecular docking studies and pharmacokinetic properties. Theoretical studies were performed by geometry optimization computation using B3LYP level at 6-311 G (d,p) basis set. The absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters were predicted and the result show that all compounds have a great ADMET profile. To study the antibacterial, anti-Mycobacterium tuberculosis activities, ciprofloxacin and its derivatives were interacted with the proteins: Thymidylate Kinase (PDB: 4QGG), Biotin carboxylase (PDB: 3JZF) and ß-lactamase BlaC (PDB: 3N7W). The results of the docking studies indicate that one pharmacophore designed presents a great inhibition behavior against gram-positive organism (4QGG) and significant interactions observed between the compound and ARG48, GLN101, ARG105 and GLU37 residues of 4QGG. Also, another derivative designed present the best inhibition against gram-negative organism (3JZF) several interactions were noticed between the compound and GLY165, ILE287, LEU278, HIS236, HIS209, MET169 and LYS159 residues of (3JZF). As well as, one designed candidate is good inhibitors for ß-lactamase (3N7W) multiple no bonded interactions were observed between the compound and SER84, ILE117, ASN186, LYS87, ARG187, ASN186 and THR251 residues of(3N7W). Molecular dynamics (MD) simulation study was also performed for 100 ns to confirm the stability behaviour of the main protein and inhibitor complexes. The MD simulation study validated the stability of three compounds in the protein binding pocket as potent binders. Natural bonding orbital analysis, reactivity indices and molecular electrostatic potential were carried out. The research finding of this study can be helpful to design a new potent antibacterial, antimycrobacterium candidate's drugs that will serve as the basis for future in vitro and in vivo research.Communicated by Ramaswamy H. Sarma.

Computer-aided analysis for identification of novel analogues of ketoprofen based on molecular docking, ADMET, drug-likeness and DFT studies for the treatment of inflammation.

Computer-based drug design is increasingly used in strategies for discovering new molecules for therapeutic purposes. The targeted drug is ketoprofen (KTP), which belongs to the family of non-steroidal anti-inflammatory drugs, which are widely used for the treatment of pain, fever, inflammation and certain types of cancers. In an attempt to rationalize the search for 72 new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines molecular docking towards COX-2 receptor (5F1A), ADMET pharmacokinetic parameters, drug-likeness rules and molecular electrostatic potential (MEP). It was found that six of the compounds analyzed satisfy with the associated values to physico-chemical properties as key evaluation parameters for the drug-likeness and demonstrate a hydrophobic character which makes their solubility in aqueous media difficult and easy in lipids. All the compounds presented good ADMET profile and they showed an interaction with the amino acids responsible for anti-inflammatory activity of the COX-2 isoenzyme. The calculation of the MEP of the six analogues reveals new preferential sites involving the formation of new bonds. Consequently, this result allowed us to understand the origin of the potential increase in the anti-inflammatory activity of the candidates. Finally, it was obtained that six compounds have a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug ketoprofen, suggesting that these compounds could become a powerful candidate in the inhibition of the COX-2 enzyme.Communicated by Ramaswamy H. Sarma.