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Different resistant strains of M. tuberculosis (Mtb) highlight the urgent need of novel anti-tubercular drugs. In mycobacteria, decaprenyl-phosphoryl-β-D-ribose 2'-oxidase (DprE1) is an appealing enzyme to target as it is involved in the biosynthesis of cell wall component arabinogalactan.1, 3-benzothiazin-4-ones (BTZs) based drugs are promising irreversible inhibitors of DprE1. However, a single point mutation of Cys387Ser in DprE1 results in the development of resistance to these drugs. Herein, we made an effort to decode the molecular mechanism of Cys387Ser DprE1 mutation associated resistance in Mtb against BTZs using different in silico techniques. Since the 3D crystal structure of mutant Cys387Ser protein is not yet been solved, thus the homology model was also developed using 4P8N as a template protein with 99.8% homology with the target protein. The computational results suggested that the factors like HOMO–LUMO energy gap, Burgi-Dunitz angle and distance support the covalent inhibition of wild DprE1 by 1, 3-benzothiazin-4-ones class of drugs, using BTZ043 as a reference drug and the same factors support the cause of resistance in case of Cys387Ser mutation. On the basis of these results, it was concluded that BTZ043 can efficiently inhibit the wild type DprE1 than mutant DprE1. [ABSTRACT FROM AUTHOR]

Herein, we report four series of mutual prodrugs of epalrestat by combining it with different antioxidants using glycine, beta-alanine, and phenylalanine as a linker and by directly linking them through an ester linkage. The designed prodrugs were subjected to pharmacophore and docking-based virtual screening to determine the susceptibility of these prodrugs to be hydrolyzed by human carboxylesterases (hCES1 and hCES2). Five best prodrugs from each series were further submitted to detailed mechanistic study of hCES1 and hCES2 based hydrolytic activation using quantum mechanics and molecular dynamics approach. Additionally, Verloop'ssterimol parameters (B1-B5, L) were calculated in order to investigate the steric constraint of prodrugs to the catalytic sites of hCES1 and hCES2 enzymes. Our results indicated that, among these prodrugs, EP-D4, EP-E13, EP-F5, and EP-F14 are best substrates for hCES1 while EP-G3 and EP-G15 are potential substrates for hCES2. On the other hand, EP-D19 serves as good substrates for both enzymes. Image 1 • Epalrestat-antioxidant mutual prodrugs were designed. • Homology model was built for hCES2. • Pharmacophore models were generated for both hCES1 and hCES2. • Molecular docking and dynamics simulations were performed. • Quantum mechanical and sterimol parameters were calculated to determine the catalytic efficiency of hCES1 and hCES2. [ABSTRACT FROM AUTHOR]

Over activated molecular target ALR2 of polyol pathway and oxidative stress are two well established pathological indicators in diabetic complications. In present study, mutual prodrugs of Epalrestat and natural product based antioxidants were designed, synthesized and evaluated. In silico techniques such as molecular dynamic simulations and quantum mechanical approaches, considering human esterase enzyme (hCE1) as the site of hydrolytic cleavage were employed in designing of these mutual prodrugs. Geometrical parameters (distance and Burgi-Dunitz angle favorable for nucleophilic attack) and quantum mechanical parameters (HOMO-LUMO energy gap), which govern the hydrolytic cleavage of ester prodrugs by esterase enzyme were calculated. Further, on the basis of in silico analysis, mutual prodrugs were synthesized and considering the values of in silico parameters, EPL-GUA ( 3g ) was evaluated for its in vivo antioxidant activity. Results suggested that 3g possess significant antioxidant activity intermediary to control and Epalrestat. Thus, this study has concluded that these mutual prodrugs could be optimized to develop molecules for the management of diabetic complications. [ABSTRACT FROM AUTHOR]

During the ongoing pandemic, there have been increasing reports of invasive fungal disease (IFD), particularly among immunocompromised populations. Candida albicans is one of the most common clinical pathogenic microorganisms which have become a serious health threat to population either infected with Covid-19 or on treatment with immunosuppressant's/broad-range antibiotics. Currently, benzothiazole is a well-explored scaffold for anti-fungal activity, especially mercapto substituted benzothiazoles. It is reported that exploring the 2nd position of benzothiazoles yield improved anti-fungal molecules. Therefore, in the current study, a lead optimization approach using a bioisosteric replacement protocol was followed to improve the anti-fungal activity of an already reported benzothiazole derivative, N -(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide. To rationally identify the putative anti-candida targets of this derivative, network analysis was carried out. Complexes of designed compounds and identified putative targets were further analyzed for the docking interactions and their consequent retention after the completion of exhaustive MD simulations. Top six designed compounds were synthesized and evaluated for in-vitro anti-fungal property against Candida, which indicated that compounds 1.2c and 1.2f possess improved and comparable anti-fungal activity to N -(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide and Nystatin, respectively. [Display omitted] [ABSTRACT FROM AUTHOR]

• Design and synthesis of quinazolin-4(3H)-one based derivatives as an optimized structure to Zenarestat. • Implimenting Scaffold hopping approach as a suggestion for bioisosteres • Subjecting to Molecular docking and Dynamics approach to understand the interaction pattern. • Screening the designed derivatives for in-silico ADMET predictions. • Evaluationof In-vitro ALR2 inhibitory activity Zenarestat withdrawal from the clinical trials owing to severe renal toxicity was a major setback in developing ALR2-targeted agents to manage diabetic complications. Addressing the toxicity issue by making some structural modifications in a well-known ALR2 inhibitor Zenarestat via a bioisosteric replacement/scaffold hopping approach can be very fruitful. This approach helps in obtaining a library of optimized analogues that can be potential ALR2 inhibitors with minimal side effect. Herein, using scaffold hoping, quinazolin-4(3H)-one was obtained as one of the top bioisostere with good BIF, shape and field scores. The designed in-house library of quinazolin-4(3H)-one was studied for their SAR profile based on the developed qualitative model via Activity atlas option. Important field points i.e., positive and negative electrostatics along with shape properties were analyzed that are crucial for ALR2 inhibitory activity. Some structure-based approaches including molecular docking and dynamics also suggested that the designed quinazolin-4(3H)-one based derivatives can be putative ALR2 inhibitors. These molecules were synthesized and evaluated for in-vitro ALR2 inhibitory activity. It was observed that compound Q2, Q3 and Q10 are most potent inhibitors with IC 50 values of 2.56 ± 0.03, 1.72 ± 0.02 and 1.47 ± 0.03 µM, respectively. Additionally, the predicted ADMET properties were also found to be favorable in comparison to Zenarestat. [ABSTRACT FROM AUTHOR]