Current Computer - Aided Drug Design - Volume 13, Issue 1, 2017

Background: The prevalence of multi-drug resistance S. aureus is one of the most challenging tasks for the treatment of nosocomial infections. Proteins and enzymes of peptidoglycan biosynthesis pathway are one among the well-studied targets, but many of the enzymes are unexplored as targets. MurE is one such enzyme featured to be a promising target. As MurE plays an important role in ligating the L-lys to stem peptide at third position that is crucial for peptidoglycan synthesis. Objective: To screen the potential MurE inhibitor by in silico approach and evaluate the best potential lead molecule by in vitro methods. Method: In the current study, we have employed structure based virtual screening targeting the active site of MurE, followed by Molecular dynamics and in vitro studies. Results: Virtual screening resulted in successful screening of potential lead molecule ((2R)-2-[[1-[(2R)- 2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan). The molecular dynamics of the MurE and Lead molecule complex emphasizes that lead molecule has shown stable interactions with active site residues Asp 406 and with Glu 460. In vitro studies demonstrate that the lead molecule shows antibacterial activity close to standard antibiotic Vancomycin and higher than that of Ampicillin, Streptomycin and Rifampicin. The MIC of lead molecule at 50μg/mL was observed to be 3.75 μg/mL, MBC being bactericidal with value of 6.25 μg/mL, cytotoxicity showing 34.44% and IC50 of 40.06μg/mL. Conclusion: These results suggest ((2R)-2-[[1-[(2R)-2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan) as a promising lead molecule for developing a MurE inhibitor against treatment of S. aureus infections.

Background: Indolizines represent a class of heteroaromatic compounds, of pharmacological importance, containing two condensed 5- and 6-memebered rings bridged by a nitrogen atom. Despite indolizine is an important medicinal moiety, a detailed view on the mechanism of action of biologically active indolizines is unavailable. Objective: The study of ligand–enzyme affinity is of high interest; description of characteristics (energetic and geometric ones) of ligand binding to the active sites of an enzyme could be useful in understanding the action mechanism of a given ligand on the concerned enzyme. Method: After conducting a QSAR study, to predict IC50 (on 15-LO protein from soybeans) of indolizine derivatives and a docking study of indolizines on Beta lactamase and Nicotinamide phosphoribosyltransferase proteins [1], a molecular dynamics analysis was performed on one of the indolizine derivatives, complexed to the above proteins. Results: The performed molecular dynamics study led to the identification of interactions responsible for the stabilization of complexes of the chosen ligand (i.e., indolizine derivative) with the considered enzymes and the specificity of the ligand interaction as well. The structural data and enthalpy values clearly indicate the differences in the behavior of ligand at the active sites of the three investigated enzymes. Among the studied proteins, the hydrophobicity of the active site of Nicotinamide phosphoribosyltransferase seems to be the main factor in promoting the interaction enzyme-ligand, much more manifested in this case, in comparison to the other two proteins Beta lactamase and Nicotinamide phosphoribosyltransferase Conclusion: The present paper discusses a possible mechanism of interaction of an indolizine derivative with three enzyme proteins, providing information for future work in this topic.

Background: Urate oxidase is absent in humans so the enzyme is considered as an important therapeutic agent to control hyperuricemic disorders. Currently available enzymes with pharmaceutical applications have adverse effects associated with allergic reactions and anaphylactic shocks, in case of chronic treatment. Therefore, developing variant forms of the enzyme, with lower immunogenicity and similar or higher activity, is of great importance. Aim: Here, we tried to improve the structure of a recently resurrected ancestral mammalian urate oxidase (which is claimed to have higher enzymatic activity compared to other mammalian counterparts) by introducing eight rational mutations and verified the consequence of these mutations on immunogenicity, stability and the affinity of protein to uric acid by computational techniques. Methods: After modeling the full-length wild-type and mutant structures, structural dynamics were monitored through 20 ns and 50 ns of molecular dynamics simulation by GROMACS software package for the structures holding and lacking uric acid, respectively. Results: Simulation results implied maintenance of 3D arrangement, volume and compactness between wild-type and mutant structures. However, residues of the mutated structure showed a higher tendency for hydrogen bond formation leading to a more stable and more soluble protein package with a higher surface area buried between protein chains. We also used the DiscoTope-2.0 server to map changes in immunogenicity index of 50 structures derived from the last 10ns of simulation. Conclusion: Finally, this study suggests a urate oxidase mutant with improved overall stability, reduced immunogenicity and slightly lower affinity for uric acid compared to the resurrected ancestral mammalian urate oxidase.

Background: The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether. Objective: This study seeks to understand, atomistic resolution, the structural and physicochemical factors influencing CYP2D6 metabolic discrimination. Method: Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the conformational dynamics of CYP2D6 following which the most populated structures were employed for ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates. Results: Using atomistic treatment at the molecular mechanics level and multiple CYP2D6 conformations for docking, two primary ligand binding subsites (subsites A and B) were identified within an otherwise extensive ligand recognition site. The studied drug molecules were found to display distinct preference for either of the two subsites. Correlation and center-of-mass distribution analysis showed subsite binding preference to depend significantly on CYP2D6 conformation, as well as molecular properties such as molecular size and number of hydrogen bond donor present in the drug molecule. Conclusion: CYP2D6 binding subsite A was found to be relatively selective for small molecular weight with higher polarity compared with subsite B which tends to favor larger molecular weight and relatively hydrophobic molecules such as tamoxifen and imipramine. Our simulations further suggest that the ability of the CYP2D6 binding site residues to sample different conformations may partly account for its ability to metabolize diverse drug classes.

Background: Docking study has become an important and interesting tool for the investigation of drug- receptor interaction. Computational methodologies have become a crucial component in the drug discovery programs which involves identification of target and lead along with their ADME and pharmacokinetic studies so as to obtain a potent lead. Objective: Synthesis and Molecular modeling investigation of some new 2-mercaptoimidazoles. Method: New 2- mercaptoimidazoles were synthesized via solid phase synthesis and were characterized by spectral studies i.e IR, 1NMR, Mass spectra and LC-MS. Compounds were screened for their antimicrobial potency via agar well diffusion assay against three bacterial strains and two fungal strains. Compounds were subjected to molecular docking studies for rationalization of their mode of action. Results: 18 new imidazole derivatives having mercapto group (4a-r) were synthesized via solid phase synthesis and were characterized by spectral studies i.e IR, 1NMR, Mass spectra and LC-MS. All the compounds were found to possess promising antimicrobial potency. However, compounds 4j and 4k were found to be the most potent compounds of the series against al the tested strains. The in silcio molecular modeling study results indicated that all the compounds exhibited good affinity towards the active site and thus may be considered as good inhibitors of enzyme 14α-demethylase. Conclusion: Thus, it may be concluded that the compounds are good inhibitors of enzyme 14α- demethylase and may be further investigated to obtain antimicrobial lead.

Background: In our previous studies of nerve conduction conducted by proton hopping, we have considered the axon, soma, synapse and the nodes of Ranvier. The role of proton hopping described the passage of information through each of these units of a typical nerve system. The synapse projects information from the axon to the dendrite and their associated spines. Methods: We have invoked the passage of protons via a hopping mechanism to illustrate the continuum of the impulse through the system, via the soma following the dendrites. This is proposed to be a continuum invoked by the proton hopping method. Results: With the proposal of the activity through the dendrites, via proton hopping, a complete model of the nerve function is invoked. At each step to the way, a water pathway is present and is invoked in the proposed model as the carrier of the message via proton hopping. The importance of the dendrites is evident by the presence of a vast number of spines, each possessing the possibility to carry unique messages through the nervous system. Conclusion: With this model of the role of dendrites, functioning with the presence of proton hopping, a complete model of the nerve system is presented. The validity of this model will be available for further studies and models to assess it’s validity.

Background: Two main factors, which have an influence on oral absorption from solid, immediate release dosage form, are solubility and permeability. These are considered the main fundamental properties that govern the rate and extent of oral absorption. The significance of these properties has been highlighted in the Biopharmaceutics Classification System (BCS). Objective: The concept of this paper was to predict the solubility and permeability of fluoroquinolones using in silico methods based on the assumptions of the BCS. An attempt was also made to determine the place within this system for drugs from the fluoroquinolone group. Method: The study was carried out with the use of modern computational techniques which developed based on Artificial Neural Network Ensembles for Binary Classification. Results: Using the values of the physicochemical descriptors of medicinal compounds with labeled BCS class, two classification models were elaborated for solubility and permeability. Conclusion: The obtained models helped to predict the provisional class for the following drugs in the BCS. Continuous improvement of computational models may support and can be treated equally with the in vivo data.

Background: Design of isoform-specific inhibitors is a major challenge in the new therapeutic agents development. Methods: The article describes the development of a robust selectivity for CA XII QSAR and 3DQSAR models of 40 benzenesulfonamide derivatives bearing pyrimidine moieties using PHASE module of Schrödinger for 3D-QSAR or E-DRAGON and R software for 2D-QSAR. Two QSAR protocols were explored: traditional (affinity) and selectivity (affinity ratio) based. Results: A total of 25 2D and 3D-QSAR models were developed using a training set of 30 compounds using the two protocols for 6 CA isoforms. A new ad hoc descriptor T(OH..Cl) was created targeting CA XII affinity. Satisfactory results were obtained in terms of model quality expressed statistically as F, R2 and R2 ADJ. Developed models were analyzed using different statistical validation techniques, both by using the Leave One Out (LOO) criterion, and by applying a model on a test set. The Applicability Domains of the 2D-QSAR models were determined. Two PHASE (affinity and selectivity) 3D-QSAR models were rationalized by manual docking of the ligands into the X-ray crystal structures. The affinity and selectivity based protocols were compared. Conclusion: This study provides insights for designing sulfonamide compounds with a better isoform selectivity.