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Enoyl‐acyl carrier protein reductase (InhA) of type II fatty acid synthase system is involved in the synthesis of mycolic acids which is a major component of the bacterial cell wall. Since they are the key enzymes playing a very significant role in the FASII pathway of the bacterium. In this study, we have developed a workflow for identification of InhA inhibitors by utilizing in silico virtual screening approaches based on various machine learning algorithms followed by pharmacophore based virtual screening. The hits screened from the models were further subjected to molecular docking. Further, based on the XP docking score best twenty compounds were subjected to molecular dynamics study. Finally, nine compounds were shortlisted on the basis of best stable ligand RMSD, c‐alpha RMSD, and RMSF plot for biological evaluation studies. Experimental validation of the shortlisted compounds identified one compound JFD01724 having potent inhibitory activity and was able to inhibit the growth of mycobacterium tuberculosis. Further medicinal chemistry efforts may help to improve the inhibitory potency of the identified compound. [ABSTRACT FROM AUTHOR]

Lysosome has been long understood as a vital digestive organelle. Increasing reports indicate that the lysosome also plays a crucial role in the pathogenesis of a variety of neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition stimulated by lysosomal dysfunction may cause age‐related neurodegeneration. Enormous efforts have been devoted to the development of effective therapeutics against Alzheimer's disease, the most debilitating neurodegenerative disease. Endopeptidase activity of the Cathepsin‐B is associated with the pathological processes. Work presented here focuses on identification of new inhibitors against Cathepsin‐B protein using diverse computational approaches together. The inhibitors identified were further tested for in‐vitro activity using enzyme based assay method. The identified inhibitors provided interesting understanding on how the water thermodynamic properties along with hydrophobic, steric, electronic, and structural requirements contribute to cathepsin‐B inhibitory activity. These water thermodynamic studies, may further be used in computer aided drug discovery pipeline to design and predict more potent derivatives of various scaffolds as cathepsin‐B inhibitors. [ABSTRACT FROM AUTHOR]

The malaria parasite carries two organelles, the apicoplast and mitochondrion, whose DNA genomes must be maintained for optimal function and parasite survival under genotoxic stress. DNA repair mechanism(s) operative within these organelles were explored by mining the Plasmodium falciparum nuclear genome for sequences encoding proteins of major DNA repair pathways with predicted targeting to either organelle. Of the panel of enzymes identified for base excision repair (BER), we characterized the apurinic/apyrimidinic (AP) endonuclease PfApn1—an EndoIV whose homolog is not known in humans. PfApn1 targeted to the mitochondrion and functioned as an AP endonuclease requiring both Zn2+ and Mn2+ ions for maximal activity. Mutation of the critical third metal‐binding site residue H542 resulted in the loss of Mn2+ (but not Zn2+) binding indicating that Mn2+ bound PfApn1 at this site; this was further supported by molecular dynamic simulation. CD spectra analysis further showed requirement of both metal ions for the attainment of PfApn1 β‐strand‐rich optimal conformation. PfApn1 also functioned as a 3′‐phosphatase that would enable removal of 3′‐blocks for DNA polymerase activity during BER. Interestingly, unlike Escherichia coli and yeast EndoIV homologs, PfApn1 lacked 3′–5′ exonuclease activity and also did not cleave damaged bases by nucleotide incision repair (NIR). Uncoupling of endonuclease/phosphatase and exonuclease/NIR in PfApn1 suggests that amino acid residues distinct from those critical for endonuclease function are required for exonuclease activity and NIR. Characterization of a critical mitochondrion‐targeted AP endonuclease provides evidence for a functional BER pathway in the parasite organelle. [ABSTRACT FROM AUTHOR]