School of Chemistry

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Browsing School of Chemistry by Author "Abdullah, Maaged"
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    Computational basis for the design of PLK-2 inhibitors
    ( 2020-02-01) Abdullah, Maaged ; Guruprasad, Lalitha
    PLK-2 is a serine/threonine protein kinase and plays a crucial role in cell cycle regulation; due to its pivotal function, this enzyme is approved as cancer drug target. We used BI-2536 a PLK-1/PLK-2 inhibitor to build a pharmacophore model and applied in the virtual screening of ZINC database to retrieve new molecules that bind the active site of PLK-2 environment with a high fit value. The molecules that do not fit the enzyme active site environment were subjected to conformation enrichment by generation of conformations in the active site environment by molecular docking, and the molecules with new scaffold that did not pass into the active site from molecular docking were subjected to molecular pruning to delete bulky substituents that prevent the molecules from binding. Molecular docking was used to find the binding pose of the selected molecules into active site of PLK-2; all screened-in hit molecules make favorable non-bonding interactions with PLK-2 active site similar to the reference inhibitor. Molecular dynamics simulations, the binding free energy calculations of the complexes, and the stability of hydrogen bonding interactions further revealed the usefulness of these screened compounds as suitable hit molecules for inhibition of PLK-2.
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    Computational fragment-based design of Wee1 kinase inhibitors with tricyclic core scaffolds
    ( 2019-02-01) Abdullah, Maaged ; Guruprasad, Lalitha
    Wee1 is cell cycle protein comprising a kinase domain and is a validated cancer target. We have designed molecules with variable tricyclic core scaffolds [6-6-5] system and extended them based on the chemical space available in the active site of Wee1 kinase using de novo drug design. The core scaffolds and linking fragments were extracted from pharmacophore-based virtual screening of ZINC and PubChem databases and Ludi library. These molecules bind the hinge region of kinase active site and form hydrogen bonds as confirmed from molecular docking, molecular dynamics simulations, and MM_PBSA calculations. When compared with reference inhibitors, AZD1775 and PHA-848125, the de novo designed molecules also show good docking scores and stability, retained non-covalent interactions, and high binding free energies contributed from active site residues.
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    Discovery of novel inhibitors of mycobacterium tuberculosis murg: Homology modelling, structure based pharmacophore, molecular docking, and molecular dynamics simulations
    ( 2018-10-17) Saxena, Shalini ; Abdullah, Maaged ; Sriram, Dharmarajan ; Guruprasad, Lalitha
    MurG (Rv2153c) is a key player in the biosynthesis of the peptidoglycan layer in Mycobacterium tuberculosis (Mtb). This work is an attempt to highlight the structural and functional relationship of Mtb MurG, the three-dimensional (3D) structure of protein was constructed by homology modelling using Discovery Studio 3.5 software. The quality and consistency of generated model was assessed by PROCHECK, ProSA and ERRAT. Later, the model was optimized by molecular dynamics (MD) simulations and the optimized model complex with substrate Uridine-diphosphate-N-acetyl-glucosamine (UD1) facilitated us to employ structure-based virtual screening approach to obtain new hits from Asinex database using energy-optimized pharmacophore modelling (e-pharmacophore). The pharmacophore model was validated using enrichment calculations, and finally, validated model was employed for high-throughput virtual screening and molecular docking to identify novel Mtb MurG inhibitors. This study led to the identification of 10 potential compounds with good fitness, docking score, which make important interactions with the protein active site. The 25 ns MD simulations of three potential lead compounds with protein confirmed that the structure was stable and make several non-bond-ing interactions with amino acids, such as Leu290, Met310 and Asn167. Hence, we concluded that the identified compounds may act as new leads for the design of Mtb MurG inhibitors.
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    Identification of 3D motifs based on sequences and structures for binding to CFI-400945, and deep screening-based design of new lead molecules for PLK-4
    ( 2021-10-01) Abdullah, Maaged ; Guruprasad, Lalitha
    PLK-4 kinase plays an essential role in the cell cycle from regulating centriole duplication till cytokinesis and is therefore an attractive drug target in cancers such as breast, lung, and central nervous system tumors. CFI-400945 is an efficient PLK-4 inhibitor and inhibits other non-PLK family proteins at nanomolar concentrations. We have compared PLK-4 with other kinases to understand its similarity based on multiple sequence alignments from protein sequences of primary structures, outer and buried residues, and compact active site conservation based on three-dimensional motifs. These in-depth studies provide information on known interface targets and design of more selective inhibitors to PLK-4. Further, pharmacophore features based on CFI-400945 bound to PLK-4 were used for searching library of compounds that were screened using deep learning methods to bind PLK-4. The shortlisted molecules were docked into PLK-4 active site and were validated using molecular docking and molecular dynamics simulations studies. MM-PBSA calculations revealed the stability of hit molecules and PLK-4 complexes in comparison with CFI-400945 and the contribution to binding from key active site residues.
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    Inhibitor binding studies of Mycobacterium tuberculosis MraY (Rv21 56c): Insights from molecular modeling, docking, and simulation studies
    ( 2019-09-22) Mallavarapu, Bala Divya ; Abdullah, Maaged ; Saxena, Shalini ; Guruprasad, Lalitha
    Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (M.tb) or tubercule bacillus, and H37Rv is the most studied clinical strain. The recent development of resistance to existing drugs is a global health-care challenge to control and cure TB. Hence, there is a critical need to discover new drug targets in M.tb. The members of peptidoglycan biosynthesis pathway are attractive target proteins for antibacterial drug development. We have performed in silico analysis of M.tb MraY (Rv2156c) integral membrane protein and constructed the three-dimensional (3D) structure model of M.tb MraY based on homology modeling method. The validated model was complexed with antibiotic muraymycin D2 (MD2) and was used to generate structure-based pharmacophore model (e-pharmacophore). High-throughput virtual screening (HTVS) of Asinex database and molecular docking of hits was performed to identify the potential inhibitors based on their mode of interactions with the key residues involved in M.tb MraY–MD2 binding. The validation of these molecules was performed using molecular dynamics (MD) simulations for two best identified hit molecules complexed with M.tb MraY in the lipid bilayer, dipalmitoylphosphatidyl-choline (DPPC) membrane. The results indicated the stability of the complexes formed and retained non-bonding interactions similar to MD2. These findings may help in the design of new inhibitors to M.tb MraY involved in peptidoglycan biosynthesis.
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    Insights into the carbonic anhydrases and autotrophic carbon dioxide fixation pathways of high CO < inf > 2 < /inf > tolerant Rhodovulum viride JA756
    ( 2018-10-01) Khandavalli, Lakshmi Venkata Naga Satya ; Lodha, Tushar ; Abdullah, Maaged ; Guruprasad, Lalitha ; Chintalapati, Sasikala ; Chintalapati, Venkata Ramana
    Biofixation of CO2 is being extensively investigated to solve the global warming problem. Purple non-sulfur bacteria are fast growers that consume CO2 and produce beneficial biomass. Better the growth at higher CO2 levels, more efficient are the strains for biofixation. Nine among fifty strains that were analyzed at elevated CO2 levels responded with better growth. Considering its enhanced growth at high CO2 and metabolic versatility, Rhodovulum viride strain JA756 was chosen to make further studies. Strain JA756 tolerates up to 50% (v/v) CO2 with its optimum between 20–40% (v/v), yielding a biomass of 3.4 g. L−1. The pattern of specific enzyme activity of carbonic anhydrase corresponded well with that of its growth. To gain insights into the genomic composition and genes related to carbonic anhydrases and CO2 fixation, draft genome sequencing of JA756 was carried out which revealed the presence of two non-homologous genes encoding for β and γ carbonic anhydrases, both of which are assumed to be implicated in maintaining intracellular inorganic carbon concentration at equilibrium. Most of the genes involved in the Calvin pathway, reductive tricarboxylic acid pathway, 3-hydroxypropionate bicycle and C4 pathways were found in the draft genome. While the experimental determinations of active roles of two of these pathways are still underway, the expression of key genes of Calvin and C4 pathway suggest their functional role in the organism. Owing to its metabolic versatility, JA756 can be advantageous for biological CO2 assimilation facilities located by the coastline, inland and also at wide ranges of CO2 concentrations.
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    Structural insights into the inhibitor binding and new inhibitor design to Polo-like kinase-1 Polo-box domain using computational studies
    ( 2019-09-02) Abdullah, Maaged ; Guruprasad, Lalitha
    Polo box domain (PBD) from Polo-Like Kinase-1 (PLK-1) a cell cycle regulator is one of the important non-kinase targets implicated in various cancers. The crystal structure of PLK-1 PBD bound to phosphopeptide inhibitor is available and acylthiourea derivatives have been reported as potent PBD inhibitors. In this work, structure and ligand-based pharmacophore methods have been used to identify new PBD inhibitors. The binding of acylthiourea analogs and new inhibitors to PBD were assessed using molecular docking and molecular dynamics simulations to understand their binding interactions, investigate the complex stability and reveal the molecular basis for inhibition. This study provides the binding free energies and residue-wise contributions to decipher the essential interactions in the protein-inhibitor complementarity for complex formation and the design of new PBD inhibitors with better binding. Communicated by Ramaswamy H. Sarma.