Semi-empirical Quantum Mechanics Research Articles

Activity Evaluation and Selection of Some Classes of Antibiotics with the use of Semi-Empirical Quantum Mechanics and Quantitative Structure- Activity Relationships Approach.

A set of β-lactam antibiotics, aminoglycoside antibiotics, and tetracycline antibiotics were proposed and analyzed with the use of Quantitative Structure-Activity Relationships (QSAR) method. The characterization of selected antimicrobial compounds in terms of both physicochemical and pharmacological on the basis of calculations of quantum mechanics and possessed biological activity data. During the study, Multiple Linear Regression (MLR) supported with Factor Analysis (FA) and Principal Component Analysis (PCA) was made, as the types of proposed chemometric approach; the semi-empirical level of in silico molecular modeling was used for calculations and comparison of molecular descriptors both in a vacuum and in the aquatic environment. The relationships between structure and microbiological activity enabled the characterization and description of the analyzed molecules using statistically significant descriptors belonging in most cases to different structural, geometric and electronic elements defining at the same time the properties of the studied three different classes of examined antibiotics. The chemometric methods used revealed the influence of some of the elements of structures examined molecules belonging to main antibiotics classes and responsible for the antimicrobial activity.

Conformation Search Across Multiple-Level Potential-Energy Surfaces (CSAMP): A Strategy for Accurate Prediction of Protein–Ligand Binding Structures

Accurate protein binding structure determination presents a great challenge to both experiment and theory. Here, in this work, we propose a new DOX protocol which combines the ensemble molecular Docking as the coarse-level, structure Optimization with the semiempirical quantum mechanics methods as the medium level, and the eXtended ONIOM ( XO) calculations as the fine level. The fundamental of the DOX protocol relies on the Conformation Search Across Multiple-level Potential-energy surfaces (CSAMP) strategy, where the conformation spaces of a funnel-like structure are searched from the coarse level with hundreds of candidates to the medium level with around 10 top candidates to the fine level with the final top 1 or 2 binding modes. An in-depth test for the protocol set up against 28 crystallographic data consisting of HMGR-statins, SDase-inhibitors, 3HNRase-inhibitors, and NA-inhibitors yielded a satisfactory result with ∼0.5 Å root-mean-square deviations (RMSDs) on geometries and ∼0.8 kcal/mol absolute error of relative binding energies on average. A further larger scale validation on the Astex test set (including 85 diverse structures) revealed an impressive performance with a RMSD < 2 Å success rate of 99%, suggesting DOX is a promising computational route toward accurate prediction of the protein-ligand binding structures.

Calculations of oxygen and humidity influence on properties of pernigraniline base polyaniline oligomers

In spite of extensive investigation and applications, influence of oxygen (O), and humidity on polyaniline (PANI) behaviour is not well understood. For this reason we have performed semi-empirical quantum mechanics, and ab-initio calculations of the pernigraniline base (PNB) PANI oligomers, of various lengths, before and after approach of H2O, O2, and hydroxyl (OH−) group, and attachment of OH− and O to various molecular positions. Structure, charge and electrostatic potential distribution, relevant energies and enthalpies, infrared and electronic spectra of the PNB tetramer equilibrium conformation, and their changes induced by specific OH−, and O attachments are determined. These results provide identification of the most probable positions for O2 and H2O approach to PNB_PANI, enthalpies of OH− and O attachments to them, changes of molecular properties induced by the attachments, and infrared and electronic modes that are most suitable for the attachments detection. The results are compared to the existing experimental data, and the results of similar calculations, and implications for the PNB_PANI applications are notified.

Host-Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations.

Relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host were calculated at the combined density-functional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 6-31G* basis set for the ligand. We employed free-energy perturbations (FEP) with the reference-potential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6-DH+ method for the ligand as an intermediate level between MM and DFT/MM to improve the convergence. Thus, the relative binding free energy of two ligands was first calculated at the MM level by an alchemical transformation from one ligand to another in both the bound and unbound states. Then, for each ligand the free-energy correction for going from the MM to the SQM/MM potentials was calculated using explicit SQM/MM MD simulations. Finally, the free-energy correction for going from the SQM/MM to the DFT/MM potentials was estimated with FEP without running any DFT/MM simulations. Instead, the free energy was calculated by single-step exponential averaging (ssEA) or employing the cumulant approximation to the second order (CA). The results show that CA converges much better than ssEA, and with 500-4500 DFT/MM single-point energy calculations, converged free energies with a precision of 0.3 kJ/mol can be obtained. These free energies reproduce the experimental binding free energy differences with a mean absolute deviation of 3.4 kJ/mol, a correlation ( R2) of 0.97, and correct signs for all of the eight free-energy differences. This is appreciably better than the results obtained at the SQM/MM level of theory and also slightly better than those obtained with MM. We show that the convergence of the SQM/MM → DFT/MM perturbations can be monitored by the use of Wu and Kofke's bias metric Π and by the standard deviation of the difference between the SQM/MM and DFT/MM energies. Finally, we show that the use of the intermediate SQM/MM MD simulations improves the convergence of the free energies by a factor of at least two, compared to doing direct MM → DFT/MM perturbations.

Improving the accuracy of predicting protein-ligand binding-free energy with semiempirical quantum chemistry charge.

Aim: It is a challenge to predict binding-free energy (ΔG) accurately. Methodology/results: For accurate ΔG prediction, a new strategy combining solvated interaction energy (SIE) or molecular mechanics/generalized Born surface area (MM/GBSA) approach with the Coulson charge of both protein and ligand calculated by semiempirical quantum mechanics (SQM), named SIE-SQMPC or MM/GBSA-SQMPC approach, was developed and tested on 50 protein-ligand complexes. Both approaches achieved higher correlation (R2) between experimental and predicted ΔG than that with Amber-ff03 charge, even for ligands with highly different scaffolds. But, SIE-SQMPC is computationally much faster than MM/GBSA-SQMPC. Conclusion: SIE-SQMPC provided an effective alternative to predict ΔG of protein-ligand binding (R2=0.66-0.94 for SIE-AM1; R2=0.59-0.98 for SIE-PM7), which has the potential of high-throughput processing for molecular docking and drug design.

Accelerated computation of free energy profile at ab initio quantum mechanical/molecular mechanical accuracy via a semi-empirical reference potential. II. Recalibrating semi-empirical parameters with force matching.

An efficient and accurate reference potential simulation protocol is proposed for producing ab initio quantum mechanical/molecular mechanical (AI-QM/MM) quality free energy profiles for chemical reactions in a solvent or macromolecular environment. This protocol involves three stages: (a) using force matching to recalibrate a semi-empirical quantum mechanical (SE-QM) Hamiltonian for the specific reaction under study; (b) employing the recalibrated SE-QM Hamiltonian (in combination with molecular mechanical force fields) as the reference potential to drive umbrella samplings along the reaction pathway; and (c) computing AI-QM/MM energy values for collected configurations from the sampling and performing weighted thermodynamic perturbation to acquire an AI-QM/MM corrected reaction free energy profile. For three model reactions (identity SN2 reaction, Menshutkin reaction, and glycine proton transfer reaction) in aqueous solution and one enzyme reaction (Claisen arrangement in chorismate mutase), our simulations using recalibrated PM3 SE-QM Hamiltonians well reproduced QM/MM free energy profiles at the B3LYP/6-31G* level of theory all within 1 kcal mol-1 with a 20 to 45 fold reduction in the computer time.

Sub-femtomolar detection of HIV-1 gene using DNA immobilized on composite platform reinforced by a conductive polymer sandwiched between two nanostructured layers: A solid signal-amplification strategy

This study introduces a signal amplification strategy rely on incorporating a specific polymer film between two typical nanostructured layers, aiming to improve the electrical properties of the platform to be able to transduce small binding event through sub-femtomolar detection of HIV-1 gene at the surface of the constructed biosensing device. The proposed composite was arrayed based on a conductive layer consist of p-aminobenzoic acid (PABA) sandwiched between the electrochemically reduced graphene oxide (ERGO) as the sub-layer, and the gold nanoparticles (AuNPs) as the interfacial layer. We computationally explored that how the use of such design enables the platform to transduce small changes in the interfacial properties of the biosensor, caused by low concentrations of HIV-1 gene, without needing any amplification strategy. Furthermore, it was found that the loin PABA conductive polymer sandwiched between two nanostructure layers play an artwork-ensemble role, which resulted in a good signal repeatability and stability during the relatively long successive incubation and detection procedures. The justification of using such an array of conductive layers was established on the attaining extra low-level of detection limit. The observed performance for probe-DNA immobilized on glassy carbon electrode (GC) modified with ERGO/PABA/AuNPs compared to the GC electrode modified with ERGO/AuNPs inspired us to perform computational calculations, a hybrid of ab-initio and semi-empirical quantum mechanics methods, to discover its probable molecular-scale reasons. A rapid single frequency impedance measurement (SFIM) was also employed to remarkably reduce the measurement time and diminish the probable nonspecific impedance changes. The proposed biosensor was used to evaluate the DNA target over an extremely wide concentration range from 0.1 fM to 10 nM, with a detection limit of 37 aM (S/N = 3).

Correction to "Testing Semiempirical QM Methods on a Data Set of Interaction Energies Mapping Repulsive Contacts in Organic Molecules".

Correction to "Testing Semiempirical QM Methods on a Data Set of Interaction Energies Mapping Repulsive Contacts in Organic Molecules".

Binding free energies in the SAMPL6 octa-acid host\u2013guest challenge calculated with MM and QM methods

We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R2) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R2 = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.

How does graphene nanosheet affect the pharmaceutical adsorption? A comprehensive insight from molecular dynamics simulation, quantum mechanics and experimental study

Tetracycline (TTC) is a type of antimicrobials that have been utilized to remedy illness. TTCs, having been released into the environs, increase the potential hazard to ecosystems and physical environments. This work has evaluated the superiority of the new generation carbon allotropes family adsorbent, graphene nanosheet (GNS) to remove TTC from the water. The pH of the adsorption system, shaking time, the initial concentration of TTC and the temperature of the solution effects were experimentally investigated. To investigate the behavior of TTC on GNS surface, the simulation of GNS and TTC was done by LAMMPS. The Semi-empirical quantum mechanics calculations were also accomplished to recognize the reliability of the MD simulation applied here. The experimental, theoretical and computational study has been performed showing TTC could be efficiently adsorbed on graphene surface via π- π interaction in low and electrostatic interactions at higher temperatures. We envisage these results to build a basis for the design of a novel system based adsorption as an economical remedy for the elimination of pharmaceuticals from wastewater. Our obtained finding is a criterion for addressing experimental work, which is generally confined by the problems associated with creating novel adsorptive systems of a specific new generation of water purification.

Revised mechanism of carboxylation of ribulose-1,5-biphosphate by rubisco from large scale quantum chemical calculations.

Here, we describe a computational approach for studying enzymes that catalyze complex multi-step reactions and apply it to Ribulose 1,5-bisphosphate carboxylase-oxygenase (Rubisco), the enzyme that fixes atmospheric carbon dioxide within photosynthesis. In the 5-step carboxylase reaction, the substrate Ribulose-1,5-bisphosphate (RuBP) first binds Rubisco and undergoes enolization before binding the second substrate, CO2 . Hydration of the RuBP.CO2 complex is followed by CC bond scission and stereospecific protonation. However, details of the roles and protonation states of active-site residues, and sources of protons and water, remain highly speculative. Large-scale computations on active-site models provide a means to better understand this complex chemical mechanism. The computational protocol comprises a combination of hybrid semi-empirical quantum mechanics and molecular mechanics within constrained molecular dynamics simulations, together with constrained gradient minimization calculations using density functional theory. Alternative pathways for hydration of the RuBP.CO2 complex and associated active-site protonation networks and proton and water sources were investigated. The main findings from analysis of the resulting energetics advocate major revision to existing mechanisms such that: hydration takes place anti to the CO2 ; both hydration and CC bond scission require early protonation of CO2 in the RuBP.CO2 complex; CC bond scission and stereospecific protonation reactions are concerted and, effectively, there is only one stable intermediate, the C3-gemdiolate complex. Our main conclusions for interpreting enzyme kinetic results are that the gemdiolate may represent the elusive Michaelis-Menten-like complex corresponding to the empirical Km (=Kc ) with turnover to product via bond scission concerted with stereospecific protonation consistent with the observed catalytic rate. © 2018 Wiley Periodicals, Inc.

Catching TFSI: A Computational-Experimental Approach to β-Cyclodextrin-Based Host-Guest Systems as electrolytes for Li-Ion Batteries.

Cyclodextrins (CDs) are pyranoside-based macromolecules with a hydrophobic cavity to encapsulate small molecules. They are used as molecular vehicles, for instance in pharmaceutical drug delivery or as solubility enhancer of monomers for their polymerization in aqueous solution. In this context, it was discovered about 10 years ago that the bis(trifluoromethylsulonyl)imide (TFSI) anion forms host-guest complexes with βCD in aqueous media. This sparked interest in using the TFSI anion in lithium-based battery electrolytes open for its encapsulation by βCD as an attractive approach to increase the contribution of the cation to the total ion conductivity. By using semi-empirical quantum mechanical (SQM) methods and the conductor-like screening model for a real solvent (COSMO-RS), a randomly methylated βCD (RMβCD) is here identified as a suitable host for TFSI when using organic solvents often used in battery technology. By combining molecular dynamics (MD) simulations with different NMR and FTIR experiments, the formation of the corresponding RMβCD-TFSI complex was investigated. Finally, the effects of the addition RMβCD to a set of electrolytes on the ion conductivity are measured and explained using three distinct scenarios.

Testing Semiempirical Quantum Mechanical Methods on a Data Set of Interaction Energies Mapping Repulsive Contacts in Organic Molecules.

Semiempirical quantum mechanical (QM) methods with corrections for noncovalent interactions provide a favorable combination of accuracy and computational efficiency that makes them a useful tool for a study of large molecular systems. It was, however, noted that the accuracy of these methods deteriorates at intermolecular distances shorter than equilibrium. In this work, we explore this issue systematically using a newly developed data set of benchmark interaction energies named R160×6. This data set maps repulsive contacts in organic molecules, and it consists of 160 model complexes for which six points along the dissociation curve are provided. Testing a wide range of semiempirical QM methods against the CCSD(T)/CBS benchmark revealed that most methods, and all the dispersion-corrected ones, underestimate the repulsion systematically. The worst cases are usually hydrogen-hydrogen contacts. The best results were obtained with PM6-D3H4 and DFTB3-D3H4, as these methods already contain a correction for the H-H repulsion, but the errors are still about twice as large as in equilibrium geometries.

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes.

Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (Ki ) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R2 of 0.56-0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications.

3-Methylthio-4-phenyl-5-phenylamino-1,2,4-triazole hexabromotellurate:X-ray and computational study

The structure of a newly synthesized 3-methylthio-4-phenyl-5-phenylamino-1,2,4-triazole 1 and its hexabromotellurate salt 2 was investigated. The X-ray diffraction study of 2 gives the insight on the different interaction types in the crystal. The DFT calculations were used for the comprehensive study of the intramolecular and intermolecular forces that are present in the title 3-methylthio-4-phenyl-5-phenylamino-1,2,4-triazole hexabromotellurate. The presence of three different aromatic moieties in the investigated compounds cause π-π stacking interactions which were studied through the Hirshfeld surface analysis and with the discrimination of weak interaction types by filling color to a reduced density gradient (RDG) function isosurface. The RDG in the crystalline state was calculated upon experimental molecular geometry by partitions of the crystal to QM part that was calculated at M06-L/6-311G(d,p) level, and the semi-empirical QM part that was modeled with the PM7 method in QM/MM-like manner. The reactivity of 3-methylthio-4-phenyl-5-phenylamino-1,2,4-triazole and its protonated form was also discussed in terms of conceptual DFT theory and it shows the tendency of sulfur to be the most active center in an electrophilic and radical attack, whereas the site for nucleophilic substitution is medium dependent and not an unequivocal. NICS(1) index was used for the analysis of aromaticity of three different cyclic moieties. The present study insights the changes in the structure of a polyfunctional substituted triazole upon its protonation and explains these changes with the analysis of weak interactions.

Modeling Alkyl p-Methoxy Cinnamate (APMC) as UV absorber based on electronic transition using semiempirical quantum mechanics ZINDO/s calculation

In this research, modeling several alkyl p-methoxy cinnamate (APMC) based on electronic transition by using semiempirical mechanical quantum ZINDO/s calculation is performed. Alkyl cinnamates of C1 (methyl) up to C7 (heptyl) homolog with 1-5 example structures of each homolog are used as materials. Quantum chemistry–package software Hyperchem 8.0 is used to simulate the drawing of the structure, geometry optimization by a semiempirical Austin Model 1 algorithm and single point calculation employing a semiempirical ZINDO/s technique. ZINDO/s calculations use a defined criteria that singly excited –Configuration Interaction (CI) where a gap of HOMO-LUMO energy transition and maximum degeneracy level are 7 and 2, respectively. Moreover, analysis of the theoretical spectra is focused on the UV-B (290-320 nm) and UV-C (200-290 nm) area. The results show that modeling of the compound can be used to predict the type of UV protection activity depends on the electronic transition in the UV area. Modification of the alkyl homolog relatively does not change the value of wavelength absorption to indicate the UV protection activity. Alkyl cinnamate compounds are predicted as UV-B and UV-C sunscreen.

Simultaneous removal of nitrogen and phosphorus by cetylpyridinium bromide modified zeolite.

In this study, surfactant modified zeolite-clinoptilolite (SMZ) by CPB (cetylpyridinium bromide) was used for simultaneous removal of ammonium, nitrate and phosphate in synthetic wastewater, and the sorption properties of SMZ were determined and compared with natural zeolite. Results showed that natural clinoptilolite had good affinity for ammonium (8.940 mg/g), but not for nitrate (0.427 mg/g) and phosphate (0.801 mg/g). With the increase of surfactant loading from 5 g/L to 40 g/L, the sorption capacity for nitrate increased from 0.462 mg/g to 4.661 mg/g. when the surfactant loading is 40 g/L, the SMZ has a phosphate adsorption capacity of 2.119 mg/g. The SMZ had a significant enhancement on nitrate and phosphate sorption, could simultaneously remove ammonium, nitrate and phosphate at specific conditions, with removal efficiency up to 85.2%, 83.1% and 56.7%, respectively. Orthogonal experiments showed that ammonium concentration was the most important factor for ammonium sorption on SMZ. Surfactant loading was the major factor for nitrate and phosphate sorption. With the increase of surfactant loading from 5 g/L to 40 g/L, the sorption capacity for nitrate increased from 0.462 mg/g to 4.661 mg/g. When the surfactant loading is 40 g/L, the SMZ has the best phosphate adsorption capacity 2.119 mg/g. Samples were characterized by X-ray diffraction (XRD) and Brunauer-Emmett-Teller (BET). Semi-empirical quantum mechanics molecular simulation indicated that electrostatic attraction existed between CPB and dihydrogen phosphate ion. Results indicate that SMZs might have great potential of removing cations and anions simultaneously in the aquatic environment, which is good for eutrophication control and nutrients removal.

Superior Performance of the SQM/COSMO Scoring Functions in Native Pose Recognition of Diverse Protein-Ligand Complexes in Cognate Docking.

General and reliable description of structures and energetics in protein–ligand (PL) binding using the docking/scoring methodology has until now been elusive. We address this urgent deficiency of scoring functions (SFs) by the systematic development of corrected semiempirical quantum mechanical (SQM) methods, which correctly describe all types of noncovalent interactions and are fast enough to treat systems of thousands of atoms. Two most accurate SQM methods, PM6-D3H4X and SCC-DFTB3-D3H4X, are coupled with the conductor-like screening model (COSMO) implicit solvation model in so-called “SQM/COSMO” SFs and have shown unique recognition of native ligand poses in cognate docking in four challenging PL systems, including metalloprotein. Here, we apply the two SQM/COSMO SFs to 17 diverse PL complexes and compare their performance with four widely used classical SFs (Glide XP, AutoDock4, AutoDock Vina, and UCSF Dock). We observe superior performance of the SQM/COSMO SFs and identify challenging systems. This method, due to its generality, comparability across the chemical space, and lack of need for any system-specific parameters, gives promise of becoming, after comprehensive large-scale testing in the near future, a useful computational tool in structure-based drug design and serving as a reference method for the development of other SFs.

Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations.

The strategy and implementation of scalable and efficient semiempirical (SE) QM/MM methods in CHARMM are described. The serial version of the code was first profiled to identify routines that required parallelization. Afterward, the code was parallelized and accelerated with three approaches. The first approach was the parallelization of the entire QM/MM routines, including the Fock matrix diagonalization routines, using the CHARMM message passage interface (MPI) machinery. In the second approach, two different self-consistent field (SCF) energy convergence accelerators were implemented using density and Fock matrices as targets for their extrapolations in the SCF procedure. In the third approach, the entire QM/MM and MM energy routines were accelerated by implementing the hybrid MPI/open multiprocessing (OpenMP) model in which both the task- and loop-level parallelization strategies were adopted to balance loads between different OpenMP threads. The present implementation was tested on two solvated enzyme systems (including <100 QM atoms) and an SN2 symmetric reaction in water. The MPI version exceeded existing SE QM methods in CHARMM, which include the SCC-DFTB and SQUANTUM methods, by at least 4-fold. The use of SCF convergence accelerators further accelerated the code by ∼12-35% depending on the size of the QM region and the number of CPU cores used. Although the MPI version displayed good scalability, the performance was diminished for large numbers of MPI processes due to the overhead associated with MPI communications between nodes. This issue was partially overcome by the hybrid MPI/OpenMP approach which displayed a better scalability for a larger number of CPU cores (up to 64 CPUs in the tested systems).

Molecular Modeling and Docking Revealed Superiority of IDX-184 As Hcv Polymerase Inhibitor

Aim: IDX-184 is a nonstructural 5b nucleoside inhibitor (NI) that was under clinical trials against HCV. This work adopts a molecular modeling approach in order to study the interaction between IDX-184 and HCV polymerase from four different genotypes. Methods: Comparisons to the native nucleotide (Guanosine triphosphate) and other NIs were performed using interaction descriptors, calculated using semiempirical quantum mechanics and molecular docking. Results: IDX-184 shows potent binding to the active site of the polymerases. In addition, IDX-184 was better than Sofosbuvir and Ribavirin when docked into polymerase active site (even with experimentally solved structure). Conclusion: Analysis of the interaction descriptors and docking complexes suggests IDX-184 as a superior NI against the studied HCV subtypes.