Chemistry Reference
In-Depth Information
In 2003 we investigated [524] nucleoside analogs that inhibit human immunodeficiency syndrome (HIV-1) reverse
transcriptase such as AZT, d4T, ddI, 3TC and ddC which are chain terminating nucleoside analogs whereas
resistance is a major problem. We appealed to atomic charges, regioselective patterns of chemical activity and other
indices of biochemical activity that could help us acquire a better understanding of how the drugs work and the
mechanism of drug resistance. The HF and DFT methods were used to investigate the above-mentioned nucleoside
analogs including diffusion, polarization and correlation effects to obtain fully optimized geometric parameters. The
effects of solvents, Mulliken and natural bond orbital charge distributions, vibrational frequencies and hydrogen
bond effects were investigated.
In 2004 we reported [525] computer-aided molecular design of novel glucosidase inhibitors for AIDS treatment. At
that time statistics suggested that some 20 million people had died and close to 40 million were living with the AIDS
disease with 14 thousands infected daily worldwide. Still, only a few pharmaceutics were available for AIDS
chemotherapy some of which acts against the virus before entrance into the host cells.
One of these targets is the glucosidase protein which depends on the activity of enzymes such as glucosidase and
transferase for the elaboration of the polysaccharides. Several glucosidase inhibitors were investigated whereas the
DFT method was used to compute atomic charges and investigate ligand/receptor interactions. Analysis of the
interactions of the proposed pharmaceutical, a pseudodisaccharide, with the Thermotoga maritime 4-alpha-
glucanotransferase in complex with modified acarbose, the scores from docking as well as the superposition of all
the ligands, suggest that our molecular designed pseudo-dissacharide may be a potent glucosidase inhibitor.
In 2004 we also reported [526] a molecular modeling and QSAR study of suppressors of the growth of Trypanasoma
cruzi epimastigotes. We used molecular modeling and QSAR tools to study 18 dithiocarbamate suppressors of the
growth of Trypanosoma cruzi epimastigotes reported in the literature as superoxide dismutase (SOD) inhibitors.
PCA (Principal component analysis) indicated that the descriptors, heat of formation, logarithm of the partition
coefficient, superficial area, charge of the nitrogen atom from the ditiocarbamate group as well as charges from the
two carbon atoms adjacent to that nitrogen are responsible for the classification between the lower and higher
trypanomacid activity. Using docking methods and multiple linear regression methods it was possible to identify the
probable bioactive isomers that suppress the growth of T. cruzi epimastiotes. Our best partial least square (PLS)
model obtained with the descriptors yields a good correlation between experimental and predicted biological
activites and compares with different SODs as possible target for interaction with the dithiocarbamates.
Quantum chemical semi-empirical AM1 and PM3 calculations were performed for the lowest energy conformations
of the compounds. The calculated variables were total energy, highest occupied molecular orbital energy (HOMO),
lowest unoccupied molecular orbital energy (LUMO), Mulliken's electronegatiity, molecular hardness, molecular
softness, atomic charges (from the electrostatic potential), bond orders, heat of formation, polarizability, dipole
moment, ionization potential, total surface area, molecular volume, octanol-water partition coefficient (Log P) as
well as other topological and three-dimensional molecular descriptors with the purpose of representing different
sources of chemical information in terms of size, shape of a molecule, symmetry and atom distribution in the
molecule.
In 2004 we also published the work density functional and docking studies of retinoids for cancer treatment [527].
The retinoic acid receptor (RAR) and retinoid X receptor (RXR) are members of the nuclear receptor superfamily.
The ligand-binding domain contains the ligand-dependent activation function. The isotypes RAR α β γ are distinct
pharmacological targets for retinoids involved in the treatment of various cancers and skin diseases. There is thus
considerable interest in synthetic retinoids with isotype selectivity and reduced side effects. We investigated the
retinoid acid receptors and three of its panagonists. We carried out DFT as well as the electrostatic potentials
calculations. Docking was used to study the interactions between the receptor and the three ligands. A theoretically
more potent inhibitor, which can be obtained by modifying one of the retinoic acids investigated, was proposed.
In 2005 we published a work on molecular dynamics, database screening, density functional and docking studies of
novel RAR ligands in cancer chemotherapy [528]. We also published in this year our results regarding a rational
desing of novel diketoacid-containing ferrocene inhibitors of HIV-1 integrase [529]. In 2005 we reported our
research on computer-aided design of a novel ligand for retinoic acid receptor in cancer chemotherapy [530]. Also in
