Structure and function of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Recently applied data visualization for multiobjective optimization techniques to CYP-mediated metabolism have revealed that CYP2D6 substrates are cationic compounds, while those of CYP2C9 are anionic (Yamashita et al. 2008). There is a clear relationship between polar surface area of ligands and binding affinity for CYP2D6, with the most potent inhibitors having a formal positive charge and a low percent polar surface area (McMasters et al. 2007). A docking study of 82 CYP2D6 substrates indicates that formal charges, number of aromatic rings, and hydrophobicity (logP) are the main attributes for CYP2D6 binding (Bazeley et al. 2006). Docking and molecular dynamics simulation studies indicate that Phe120, Glu216, Asp301, and Phe483, along with Phe219 and Glu222, are the binding residues for CYP2D6 inhibitors (Ito et al. 2008).
HIV Integrase Inhibitors
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
An MSA based 3D-QSAR study on a set of 36 styrylquinoline derivatives was reported by Leonard and Roy (2008) using 3′-processing inhibitory SAR data of these compounds (Mekouar et al. 1998; Zouhiri et al. 2000). K-means clustering was used to classify the molecules based on their topological and structural descriptors in order to divide the dataset into a training and test set. Spatial, MSA, thermodynamic, and structural descriptors were considered for the MSA model development. Several statistical techniques were used to develop the models: stepwise regression, GFA, factor analysis-MLR (FA-MLR), factor analysis-PLS (FA-PLS), and G/PLS. The stepwise regression, GFA, FA-MLR, and FA-PLS models were of comparable quality. These models revealed that molecules with high total polar surface area and relative polar surface area descriptor values have greater inhibition activity, whereas molecules with higher values in the relative hydrophobic surface area, fractional area of the molecular shadow in the XZ plane, and relative positive charge descriptors resulted in reduced inhibition activity.
Computer-Aided Drug Design for the Identification of Multi-Target Directed Ligands (MTDLs) in Complex Diseases: An Overview
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
In this approach, multiple fragments with known binding capability against individual targets of interest are combined to design a MTDL. Here, according to the “rule-of-three,” fragments are defined as molecules with a molecular weight < 300, H-bond acceptors and donors ≤ 3, and a log P ≤ 3 (Congreve et al., 2003). Additionally, number of rotatable bonds ≤ 3 and a polar surface area ≤ 60 can be used as extra parameters. Fragment-based approach for designing MTDLs can be performed using any one of the following strategies (Bottegoni et al., 2012): Chimera: linking of the key pharmacophoric functions by means of suitable spacersFusion: blending of the key functions without adding or missing any substructureHybrid: amalgamation of the requisite pharmacophoric features into one molecule
Imidazothiazole-based potent inhibitors of V600E-B-RAF kinase with promising anti-melanoma activity: biological and computational studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Hanan S. Anbar, Mohammed I. El-Gamal, Hamadeh Tarazi, Bong S. Lee, Hong R. Jeon, Dow Kwon, Chang-Hyun Oh
n = 22, F-Statistic = 41.33, R2 = 0.907, Q2LOO = 0.852, s = 0.238 where, ACDODO is a 3D-pharmacophoric descriptor based on the triplets of pharmacophoric points, where it represents an Acceptor-Donor-Donor triplet. IW2 is the INTEGY (INTEraction enerGY) moment presented as vector pointing from centre of mass to the centre of the hydrophilic region, Low INTEGY descriptors such as IW2 indicates the hydrophilic moieties are either close to the centre of mass or they balance at an opposite ends of the molecule. DD8 is the difference between the maximum hydrophobic volumes (obtained upon variation of ligand conformations) and the hydrophobic volume (D8) of the imported 3D structure calculated at the 8 levels of energy. Furthermore, the hydrophobic volume (D8) is the molecular envelope generating attractive hydrophobic interactions calculated using the DRY-probe at an energy range of −1.6 kcal/mol. PSA is the Polar Surface Area calculated via the sum of polar region contributions.
An explorative study on Staphylococcus aureus MurE inhibitor: induced fit docking, binding free energy calculation, and molecular dynamics
Published in Journal of Receptors and Signal Transduction, 2019
Mohammed Afzal Azam, Niladri Saha, Srikanth Jupudi
The RMSD of ligand decreased till 18-ns and then stabilized in the range 1.60–2.7 Å, indicating less conformational flexibility and stability of ligand within the catalytic pocket (Supplementary Figure S9). The radius of gyration (rGyr), which measures the extendness of ligand decreased during simulation till 18-ns and then stabilized at lower window in the range 4.56–5.52 Å, further indicating the stability of ligand during MD simulation. The SASA of inhibitor 1 increased sharply up to 14-ns (180–360 Å2) and then stabilized at lower window of 100–270 Å2, indicating the burial of inhibitor within the catalytic pocket during last 16-ns of MD simulation. The polar surface area (PSA), which is a measure of molecular surface arising from polar atoms (nitrogen and oxygen atom), remains stable in the narrow range of 281–309 Å2, further indicating the burial of polar groups within the catalytic pocket.
Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Samar El-Kalyoubi, Samiha A. El-Sebaey, A. M. Rashad, Hanan A. AL-Ghulikah, Mostafa M. Ghorab, Sherin M. Elfeky
Several parameters, including structural, molecular, and physicochemical properties expressed in Lipinski’s rule, should be considered. Lipinski’s rule (rule of five) represents broad and general guidelines for orally bioavailable drug candidates, which include the following parameters: molecular weight (M. wt. ≤ 500 g/mol), number of hydrogen bond acceptors ≤ 5, number of hydrogen bond donors ≤ 10, and partition coefficient (log P) ≤561. Topological polar surface area (TPSA), which is another important physicochemical property that needs to be studied for drug candidates, is used to express the surface associated with polar atoms, ideally TPSA ≤ 16062. Similar to 5-fluorouracil, both compounds 3a and 5d showed no violation of Lipinskìs rule, with molecular weights ranging from 305.19 g/mol to 354.40 g/mol. Furthermore, compounds 3a and 5d had acceptable partition coefficients and topological polar surface areas ranging from −0.61 to 2.09 and 54.86 to 109.98, respectively, whereas log p and TPSA of 5-fluorouracil were −0.73 and 65.72, respectively. Moreover, both compounds had 2 to 4 rotatable bonds, 2 to 3 hydrogen bond acceptors, and 1 to 3 hydrogen bond donors following Lipinskìs rule of five (Table 8).
Related Knowledge Centers
- Central Nervous System
- Molecule
- Oxygen
- Nitrogen
- Chemical Polarity
- Medicinal Chemistry
- Blood–Brain Barrier
- Biopharmaceutics Classification System
- Cheminformatics
- Chemistry Development Kit