Water network chemistry to exploit the nature of catalytic water molecules in Mtb DNA gyrase: a computational study to understand the binding mechanism of fluoroquinolones.

The dynamics of DNA gyrase and mutants of DNA gyrA such as G88A, A90V, S91P, D94A, D94G, D94N, D94Y; and double-point mutant (S91P-D94G), are meticulously investigated using computational approaches. Molecular dynamics (MD) and hydration thermodynamics have shed light on the fundamental, mechanistic basis of mutations on the conformational stability of Quinolone Binding Pocket (QBP) of DNA gyrase. Analysis of MD results revealed the displacement of a single crystal water molecule (HOH201) from the catalytic site of wild-type (WT) and mutants of DNA gyrA. This prompted our research group to probe the five crystal water molecules present in the QBP of the enzyme using water thermodynamics. Hydration thermodynamics analysis revealed the displacement of HOH201 due to unstable thermodynamic signatures. Further, the analysis highlighted significant changes in thermodynamic signatures and locations of five crystal water hydration sites upon mutation. Integrated MD simulations and water thermodynamics provided promising insights into the conformational changes and inaccessibility of the catalytic water molecule that can influence the design of DNA gyrase inhibitors.Communicated by Ramaswamy H. Sarma.

Rapid structure-based identification of potential SARS-CoV-2 main protease inhibitors.

The COVID-19 outbreak has thrown the world into an unprecedented crisis. It has posed a challenge to scientists around the globe who are working tirelessly to combat this pandemic. We herein report a set of molecules that may serve as possible inhibitors of the SARS-CoV-2 main protease. To identify these molecules, we followed a combinatorial structure-based strategy, which includes high-throughput virtual screening, molecular docking and WaterMap calculations. The study was carried out using Protein Data Bank structures 5R82 and 6Y2G. DrugBank, Enamine, Natural product and Specs databases, along with a few known antiviral drugs, were used for the screening. WaterMap analysis aided in the recognition of high-potential molecules that can efficiently displace binding-site waters. This study may help the discovery and development of antiviral drugs against SARS-CoV-2.

Computational and Biological Investigations on Abl1 Tyrosine Kinase: A Review.

Abl1 tyrosine kinase is a validated target for the treatment of chronic myeloid leukemia. It is a form of cancer that is difficult to treat and much research is being done to identify new molecular entities and to tackle drug resistance issues. In recent years, drug resistance of Abl1 tyrosine kinase has become a major healthcare concern. Second and third-generation TKI reported better responses against the resistant forms; still they had no impact on long-term survival prolongation. New compounds derived from natural products and organic small molecule inhibitors can lay the foundation for better clinical therapies in the future. Computational methods, experimental and biological studies can help us understand the mechanism of drug resistance and identify novel molecule inhibitors. ADMET parameters analysis of reported drugs and novel small molecule inhibitors can also provide valuable insights. In this review, available therapies, point mutations, structure-activity relationship and ADMET parameters of reported series of Abl1 tyrosine kinase inhibitors and drugs are summarised. We summarise in detail recent computational and molecular biology studies that focus on designing drug molecules, investigation of natural product compounds and organic new chemical entities. Current ongoing research suggests that selective targeting of Abl1 tyrosine kinase at the molecular level to combat drug resistance in chronic myeloid leukemia is promising.

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches.

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention. Interactions made by potent allosteric inhibitor in the presence of PTP1B were studied using Molecular Dynamics (MD). Computationally optimized models were used to build separate pharmacophore models of PTP1B and TCPTP, respectively. Based on the nature of interactions the target residues offered, a receptor based pharmacophore was developed. The pharmacophore considering conformational flexibility of the residues was used for the development of pharmacophore hypothesis to identify potentially active inhibitors by screening large compound databases. Two pharmacophore were successively used in the virtual screening protocol to identify potential selective and permeable inhibitors of PTP1B. Allosteric inhibition mechanism of these molecules was established using molecular docking and MD methods. The geometrical criteria values confirmed their ability to stabilize PTP1B in an open conformation. 23 molecules that were identified as potential inhibitors were screened for PTP1B inhibitory activity. After screening, 10 molecules which have good permeability values were identified as potential inhibitors of PTP1B. This study confirms that selective and permeable inhibitors can be identified by targeting allosteric site of PTP1B.

Crystal structures and conformational analyses of three pyranochromene derivatives.

The title compounds, C27H20O6, (I) [systematic name: methyl 7-oxo-14-phenyl-1H,7H,14H-pyrano[3,2-c:5,4-c']dichromene-14a(6bH)-carboxyl-ate], C24H22O5, (II) [systematic name: methyl 1-oxo-6-phenyl-2,3,4,12b-tetra-hydro-1H,6H-chromeno[3,4-c]chromene-6a(7H)-carboxyl-ate], and C25H23N3O4, (III) [systematic name: 6-(4-ethyl-phen-yl)-2,4-dimethyl-1,3-dioxo-2,3,4,12b-tetra-hydro-1H,6H-chromeno[4',3':4,5]pyrano[2,3-d]pyrimidine-6a(7H)-carbo-nitrile], are pyran-ochromene derivatives. The central pyran rings (B) of compounds (I) and (III) adopt half-chair conformations, whereas that of compound (II) adopts a sofa conformation. The pyran rings (A) of the chromene ring systems of compounds (II) and (III) adopt half-chair conformations, while that of compound (I) adopts a sofa conformation. The mean plane of the central pyran rings (B) make dihedral angles of 70.02 (6), 61.52 (6) and 69.12 (7)°, respectively, with the mean planes of the chromene moieties (C+A) of compounds (I), (II) and (III). The bicyclic coumarin ring system (C+A+B+E) in compound (I) is almost planar (r.m.s. deviation = 0.042 Å). The carbo-nitrile side chain in compound (III) is very nearly linear, with the C-C N angle being 176.6 (2)°. The cyclo-hexene ring (E), fused with the central pyran ring (B) in compound (II) adopts a sofa conformation. In the mol-ecular structures of compounds (II) and (III), there are C-H⋯O short contacts, which generate S(7) ring motifs. In the crystal structures of the title compounds, mol-ecules are linked by C-H⋯O hydrogen bonds, which generate mol-ecular sheets parallel to the ab plane, with R 4 (3)(28) loops in (I), inversion dimers with R 2 (2)(10) loops in (II) and chains along [010] with R 2 (2)(12) ring motifs in (III). In the crystal structures of (I) and (III), there are also C-H⋯π inter-actions present, leading to the formation of a three-dimensional framework in (II) and to sheets parallel to (101) in (III).

Application of solution processable squaraine dyes as electron donors for organic bulk-heterojunction solar cells.

New low bandgap small molecules based on a squaraine (SQ) chromophore, bis[4-(2,6-di-tert-butyl)vinylpyrylium]squaraine (TBU-SQ), bis[2,6-di-tert-butyl-4-(prop-1-en-2-yl)pyrylium]squaraine (MeTBU-SQ) and bis[4-(but-1-en-2-yl)-2,6-di-tert-butylpyrylium]squaraine (EtTBU-SQ), were synthesized and used as electron donors along with PC70BM for their application in solution processed organic bulk-heterojunction (OBHJ) solar cell (SC). The long wavelength of these SQ dyes are located in between 650-750 nm in thin films and the optical bandgaps are about 1.64, 1.52 and 1.48 eV, respectively. The electrochemical properties of these SQ dyes indicate that they are well suited for the fabrication of OBHJSCs as electron donors along with fullerene derivatives as electron acceptors. The OBHJ photovoltaic (PV) devices fabricated with the blend of TBU-SQ:PC70BM, MeTBU-SQ:PC70BM and EtTBU-SQ:PC70BM cast from chloroform (CF) solvent exhibited a power conversion efficiency (PCE) of 1.71%, 2.15%, and 1.89%, respectively. The PCE of the OBHJSCs based on MeTBU-SQ:PC70BM blends cast from DIO-THF (DIO = 1,8-diiodooctane) additive solvent and cast from DIO-THF with subsequent thermal annealing have been further improved up to 2.73% and 3.14%, respectively. This enhancement in the PCE is attributed to the improvement in the crystalline nature of the blend and more balanced charge transport resulting from the higher hole mobility. All these results have been supported by the quantum chemical calculations.