Cosolvent Sites-Based Discovery ofMycobacterium TuberculosisProtein Kinase G Inhibitors

Abstract

Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein–ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis ( Mtb ). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages.

Structure–Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

“…Therefore, we hypothesized that the serine/threonine protein kinases in Mtb might be their potential targets. Up to now, there are 11 known serine/threonine protein kinases in Mtb , three of which, PknA, PknB, and PknG, are essential for Mtb survival. , Several PknB inhibitors were reported and shared a similar molecular scaffold with our synthesized compounds . Therefore, differential scanning fluorescence (DSF) assay was performed to identify the interactions of representative compound 5a and purified Mtb PknB protein.…”

Catalyst‐free oxidative [3+2]‐annulation of (2‐nitroethene‐1,1‐diyl)bis(methylsulfane) and pyridinium ylides: Efficient synthesis of (methylsulfanyl)indolizines heterocycles

“…fantofarone (V) is a calciumchannel blocker used in the treatment of vasospasms [10]. Compounds IV, VI, and VII have shown strong antitubercular activity [11], antihistaminic activity [12], and antidiabetic activity [13].…”

Solvent Sites Improve Docking Performance of Protein–Protein Complexes and Protein–Protein Interface-Targeted Drugs

“…SSs were identified and characterized using our well-tested strategy. 11,24 Sites were calculated using a script created by our group (https://doi.org/10.5281/zenodo.5647767) 31 considering all residues within 4 Å of ligand (detailed in Table S2) and over all of the frames from the MD (1000 for EtOH and 2500 for PhOH), besides the following parameters: distance of 0.30 Å (-dist) and at least 7.5% of total frames for EtOh and 6% for PhOH (-watNmin) for each replicate. Once determined, we classified the sites according to polar (i.e., H-bond donor or acceptors) as defined by the WSs, as well as ethanol −OH and phenol −OH sites, HS as defined by the ethanol −CH 3 probe, and finally PhS as defined by the phenol aromatic ring.…”