Abstract
Carbonic anhydrases (CA) inhibitory action could be linked to the treatment of a number of ailments, including cancer, osteoporosis, glaucoma, and several neurological problems. For the development of effective CA inhibitors, a variety of heterocyclic rings have been investigated. Furthermore, at high altitudes, oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species, and CA inhibitors having role in combating this oxidative stress. Acetazolamide contains thiadiazole ring, which has aroused researchers’ interest because of its CA inhibitory action. In the present study, we used a number of drug design tools, such as pharmacophore modeling, 3D QSAR, docking, and virtual screening on twenty-seven 1,3,4-thiadiazole derivatives that have been described as potential CA inhibitors in the literature. An atom-based 3D-QSAR analysis was carried out to determine the contribution of individual atoms to model generation, while a pharmacophore mapping investigation was carried out to find the common unique pharmacophoric properties required for biological activity. The coefficient of determination for both the training and test sets were statistically significant in the generated model. The best QSAR model was chosen based on the values of R2 (0.8757) and Q2 (0.7888). A molecular docking study was also conducted against the most potent analogue 4m, which has the highest SP docking score (−5.217) (PDB ID: 6g3v). The virtual screening revealed a number of promising compounds. The screened compound ZINC77699643 interacted with the amino acid residues, Pro201 and Thr199, in the virtual screening study (PDB ID: 6g3v). These interactions demonstrated the significance of the CA inhibitory activity of the compound. Furthermore, ADME study revealed useful information regarding compound’s drug-like properties. Therefore, the findings of the present investigation could aid in the development of more potent CA inhibitors, which could benefit the treatment of oxidative stress at high altitudes.
Highlights
Oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species (RONS), which have been linked to a variety of oxidative stress related diseases [1,2]
The formation of reactive oxygen and nitrogen species (RONS) causes oxidative damage to biomolecules such as protein and DNA, which has been linked to a number of diseases [3,4,5,6]
Physical activity can sometimes cause an increase in oxidative stress, fatigue, headaches, nausea, anorexia, and poor sleep
Summary
Oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species (RONS), which have been linked to a variety of oxidative stress related diseases [1,2]. The body’s antioxidant enzymes system becomes unresponsive At this height, the RONS-producing sources, which include various mitochondrial transport systems, nitric oxide synthase, and xanthine oxidase, become activated [7,8,9,10]. A number of medications are available to treat oxidative stress, including carbonic anhydrase (CA) inhibitors [11] and, in particular, acetazolamide [12]. Carbonic anhydrases (CAs, EC 4.2.1.1) encode bacteria found in three different genetic families, the α-, β-, and γ-classes These metalloenzymes interfere with pH regulation and other important physiological processes in these organisms by equilibrating CO2 and bicarbonate. Earlier findings suggested that acetazolamide drug can be taken as reference to produce different hypothetical compounds followed by their docking studies against CA enzyme target. We expect this effort to provide some interesting molecules for the treatment of oxidative stress linked to a variety of pathological complications [20]
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