PAPERS BY CHS STAFF IN RESEARCHGATE - FIRST AUTHOR OR CO - AUTHORED May 2015 Mahmoud Soliman ( 8 papers ) 1 . Anti - Cancer Glycosidase Inhibitors from Natural Products : A Computational and Molecular Modelling Perspective

The implementation of computational tools in pharmaceutics has proven an effectual strategy in creating harmony between the physical and chemical aspects of proteins and potential inhibitors. This is achieved by bringing to life the three dimensional retrospect of biological systems, which takes into consideration computational approaches such as quantum mechanics and molecular dynamics to facilitate drug design and discovery. In this work, we aim to provide a summary of the computational aspects of naturally derived anti-cancer inhibitors targeting the enzyme family of glycosidases. Our study offers insight into the evolution of drug discovery, molecular modelling and molecular binding modes of natural product inhibitors associated with glycosidase enzymes 2. Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations Soumendranath Bhakat, Suri Moonsamy, Mahmoud Soliman and Ross Walker Cell biochemistry and biophysics (Impact Factor: 2.38). 05/2015 ABSTRACT Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA) and residue interaction network (RIN) analysis were employed in order to investigate the atomistic basis of the mystery of why the M184I single mutation leaves the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused; (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild type, (3) variation in the overall enzyme motion as evident from the PCA for both systems and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor.Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA) and residue interaction network (RIN) analysis were employed in order to investigate the atomistic basis of the mystery of why the M184I single mutation leaves the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused; (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild type, (3) variation in the overall enzyme motion as evident from the PCA for both systems and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance. 3. Antipyrine–gamma cyclodextrin inclusion complex: Molecular modeling, preparation, characterization and cytotoxicity studies Ramesh Gannimani, Amanda Perumal, Muthusamy Ramesh, Karen Pillay, Mahmoud Soliman, Patrick Govender Journal of Molecular Structure (Impact Factor: 1.6). 05/2015; 1089:38-47. DOI: 10.1016/j.molstruc.2015.02.017 ABSTRACT A new inclusion complex for antipyrine with c-cyclodextrin was prepared by freezedrying method. Molecular modeling approach revealed most favorable conformation of inclusion complex. The inclusion complex was characterized by solid state analytical techniques and NMR spectroscopy. The complex did not exhibit toxicity up to 500 lM concentration against MDCK-1 cells. g r a p h i c a l a b s t r a c t a b s t r a c t Molecular docking, semi-empirical and molecular dynamics studies were conducted for a, b and c-cyclodextrin-associated inclusion complexes of antipyrine. The results of molecular modeling were systematically analyzed to determine the stability of inclusion complexes. In preliminary computational screening, b and c-cyclodextrin inclusion complexes of antipyrine were found to be more stable as compared to a-cyclodextrin based on docking score and binding free energies. Further, inclusion complex of antipyrine with c-cyclodextrin was prepared by freeze drying method. Formation of the inclusion complex was investigated by solid state characterization techniques such as thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy. The changes observed in decomposition temperature, diffractogram, vibrational frequencies and morphological appearance confirmed the formation of inclusion complex. In addition, results from 1 H NMR and 2D NOESY studies supported the inclusion phenomenon. The results obtained from computational studies were found to be in consistent with experimental data to ascertain the encapsulation of antipyrine into c-cyclodextrin. The inclusion complex was found to be non-toxic toward MDCK-1 cell lines. Thus, this approach may be helpful in the formulation of drug molecules using cyclodextrins. 4. In Silico Identification of Irreversible Cathepsin B Inhibitors as AntiCancer Agents: Virtual Screening, Covalent Docking Analysis and Molecular Dynamics Simulations Mbatha Sbongile, Mahmoud Soliman Combinatorial Chemistry & High Throughput Screening (Impact Factor: 1.93). 05/2015; 18(4). DOI: 10.2174/1386207318666150305154621