Publications by authors named "Jurica Novak"

11 Publications

  • Page 1 of 1

Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin-1,2,4-triazole scaffolds.

Arch Pharm (Weinheim) 2021 Mar 3:e2000473. Epub 2021 Mar 3.

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Prayagraj, Uttar Pradesh, India.

Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine-1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods ( H and C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure-activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.
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http://dx.doi.org/10.1002/ardp.202000473DOI Listing
March 2021

Simulation of UV absorption spectra and relaxation dynamics of uracil and uracil-water clusters.

Phys Chem Chem Phys 2021 Feb;23(4):2594-2604

Department of Physical Chemistry, Ruđer Bošković Institute, Zagreb, Croatia.

Despite many studies, the mechanisms of nonradiative relaxation of uracil in the gas phase and in aqueous solution are still not fully resolved. Here we combine theoretical UV absorption spectroscopy with nonadiabatic dynamics simulations to identify the photophysical mechanisms that can give rise to experimentally observed decay time constants. We first compute and theoretically assign the electronic spectra of uracil using the second-order algebraic-diagrammatic-construction (ADC(2)) method. The obtained electronic states, their energy differences and state-specific solvation effects are the prerequisites for understanding the photodynamics. We then use nonadiabatic trajectory-surface-hopping dynamics simulations to investigate the photoinduced dynamics of uracil and uracil-water clusters. In contrast to previous studies, we found that a single mechanism - the ethylenic twist around the C[double bond, length as m-dash]C bond - is responsible for the ultrafast component of the nonradiative decay, both in the gas phase and in solution. Very good agreement with the experimentally determined ultrashort decay time constants is obtained.
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http://dx.doi.org/10.1039/d0cp05618aDOI Listing
February 2021

Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database.

Future Med Chem 2021 02 8;13(4):363-378. Epub 2021 Jan 8.

Higher Medical & Biological School, Laboratory of Computational Modeling of Drugs, South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk 454080, Russia.

The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.
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http://dx.doi.org/10.4155/fmc-2020-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798421PMC
February 2021

Electronic properties investigation of human dihydrofolate reductase complexes with ligands.

J Biomol Struct Dyn 2020 Dec 21:1-16. Epub 2020 Dec 21.

Department of Chemistry, College of Science, Deanship of Scientific Research, Taif University, Taif, Saudi Arabia.

Despite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. In the focus of this study are complexes of human dihydrofolate reductase (hDHFR) with a series of known inhibitors bound in the active site. Further, a statistical analysis was performed to establish the relationships between a myriad electronic characteristics and IC. The change in total volume and the change of own electrons number of hydrogen atoms in their atomic basins are identified as the descriptors correlating the most with the hDHFR inhibition potency. Additionally, two lipophilic parts of protein (Thr56, Ser59, Ile60 and Ile7, Val8, Ala9) were found, which act as a key factor in decreasing bioactivity. The depth analysis of intermolecular interactions showed that the interactions between water molecules and ligand play a crucial role in hDHFR inhibition. Furthermore, the molecular dynamics simulations were used for deeper understanding of the structural inhibition, each for 50 ns time scale in explicit water conditions. Thus, the AlteQ approach made it possible to determine the factors influencing the activity and evaluate them not only qualitatively, but also quantitatively. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1861985DOI Listing
December 2020

Structural isomers of saligenin-based β2-agonists: synthesis and insight into the reaction mechanism.

Org Biomol Chem 2020 Dec 21;18(47):9675-9688. Epub 2020 Nov 21.

Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.

Salmeterol and albuterol are well-known β2-adenoreceptor agonists widely used in the treatment of inflammatory respiratory diseases, such as bronchial asthma and chronic obstructive pulmonary disease. Here we report the preparation of structural isomers of salmeterol and albuterol, which can be obtained from the same starting material as the corresponding β2-agonists, depending on the synthetic approach employed. Using 1D and various 2D NMR measurements, we determined that the structure of prepared isomers holds the β-aryl-β-aminoethanol moiety, in contrast to the α-aryl-β-aminoethanol moiety found in salmeterol and albuterol. We investigated the reaction of β-halohydrin and amines responsible for the formation of β-aryl-β-amino alcohol - both experimentally and using computational methods. The structure of β-halohydrin with the methyl salicylate moiety imposes the course of the reaction. The solvent plays a relevant, yet ambiguous role in the direction of the reaction, while the strength of the base influences the reaction yield and isomer ratio in a more evident way. Using computational methods, we have shown that the most probable reaction intermediate responsible for the formation of the unexpected isomer is the corresponding para-quinone methide, which can be formed due to phenol present in the methyl salicylate moiety. After successful preparation of albuterol and salmeterol isomers, we tested their inhibition potency to human acetylcholinesterase (AChE) and usual and atypical butyrylcholinesterase (BChE). Kinetic studies revealed that both isomers are low-potency reversible inhibitors of human cholinesterases.
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http://dx.doi.org/10.1039/d0ob02095hDOI Listing
December 2020

Novel radial distribution function approach in the study of point mutations: the HIV-1 protease case study.

Future Med Chem 2020 06 22;12(11):1025-1036. Epub 2020 Apr 22.

Higher Medical & Biological School, Laboratory of Computational Modeling of Drugs, South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk, 454080, Russia.

Mutations are one of the engines of evolution. Under constant stress pressure, mutations can lead to the emergence of unwanted, drug-resistant entities. The radial distribution function weighted by the number of valence shell electrons is used to design quantitative structure-activity relationship (QSAR) model relating descriptors with the inhibition constant for a series of wild-type HIV-1 protease inhibitor complexes. The residuals of complexes with mutant HIV-1 protease were correlated with the energy of the highest occupied molecular orbitals of the residues introduced to enzyme via point mutations. Successful identification of residues Ile3, Asp25, Val32 and Ile50 as the one whose substitution influences the inhibition constant the most, demonstrates the potential of the proposed methodology for the study of the effects of point mutations.
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http://dx.doi.org/10.4155/fmc-2020-0042DOI Listing
June 2020

Performance of radial distribution function-based descriptors in the chemoinformatic studies of HIV-1 protease.

Future Med Chem 2020 02 27;12(4):299-309. Epub 2020 Jan 27.

Computer-Chemie-Centrum, Friedrich-Alexander-University Erlangen-Nürnberg, Naegelsbachstr. 25, 91052, Erlangen, Germany.

This letter investigates the role of radial distribution function-based descriptors for design of new drugs. The multiple linear regression models for HIV-1 protease and its complexes with a series of inhibitors were constructed. A detailed analysis of major atomic contributions to the radial distribution function descriptor weighted by the number of valence shell electrons identified residues Arg8, Asp29 and residues of the catalytic triad as crucial for the correlation with the inhibition constant, together with residues Asp30 and Ile50, whose mutations are known to cause an emergence of drug resistant variants. This study demonstrates an easy and fast assessment of the activity of potential drugs and the derivation of structural information of their complexes with the receptor or enzyme.
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http://dx.doi.org/10.4155/fmc-2019-0241DOI Listing
February 2020

The Influence of Hydrogen atoms on the Performance of Radial Distribution Function Based Descriptors in the Chemoinformatic Studies of HIV-1 Prote-ase Complexes with Inhibitors.

Curr Drug Discov Technol 2020 Jan 2. Epub 2020 Jan 2.

South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk 454080, Russian Federation.

In this letter the newly introduced approach based on the radial distribution function (RDF) weighted by the number of va-lence shell electrons is applied for a series of HIV-1 protease enzyme and its complexes with inhibitors to evaluate the influ-ence of hydrogen atoms on the performance of the model. The multiple linear regression method was used for the selection of the relevant descriptors. Two groups of residues having dominant contribution to the RDF descriptor are identified as relevant for the inhibition. In the first group are residues like Arg8, Asp25, Thr26, Gly27 and Asp29, which establish direct interaction with the inhibitor, while the second group consists of the amino acids at the interface of the two homodimer sub-units or with the solvent. The crucial motif pointed out by our approach as the most important for inhibition of the enzyme's activity and present in all inhibitors is hydroxyl group that establish hydrogen bond with Asp25 side chain. Additionally, the comparison to the model without hydrogen showed that both models are of similar quality, but the downside of the current model is the need for the determination of residues' protonation states.
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http://dx.doi.org/10.2174/1570163817666200102130415DOI Listing
January 2020

New Brush-Type Chiral Stationary Phases for Enantioseparation of Pharmaceutical Drugs.

Molecules 2019 Feb 25;24(4). Epub 2019 Feb 25.

Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb 10000, Croatia.

The importance of chirality in drug development is unquestionable, with chiral liquid chromatography (LC) being the most adequate technique for its analysis. Among the various types of chiral stationary phases (CSPs) for LC, brush-type CSPs provide the base for interaction analysis of CSPs and enantiomers, which provide valuable results that can be applied to interaction studies of other CSP types. In order to analyze the influence of aromatic interactions in chiral recognition, we designed a set of ten new brush-type CSPs based on ()--(1-aryl-propyl)-3,5-dinitrobenzamides which differ in the aromatic unit directly linked to the chiral center. Thirty diverse racemates, including several nonsteroidal anti-inflammatory drugs and 3-hydroxybenzodiazepine drugs, were used to evaluate the prepared CSPs. Chromatographic analysis showed that the three new CSPs separate enantiomers of a wide range of compounds and their chromatographic behavior is comparable to the most versatile brush-type CSP-Whelk-O1. The critical role of the nonbonding interactions in positioning of the analyte (naproxen) in the cleft of , as well as the analysis of interactions that make enantioseparation possible, were elucidated using computational methods. Furthermore, the influence of acetic acid as a mobile phase additive, on this enantiorecognition process was corroborated by calculations.
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http://dx.doi.org/10.3390/molecules24040823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412842PMC
February 2019

Photochemistry of 1- and 2-Naphthols and Their Water Clusters: The Role of ππ*(L ) Mediated Hydrogen Transfer to Carbon Atoms.

Chemistry 2017 Jun 19;23(34):8244-8251. Epub 2017 May 19.

Department of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10000, Zagreb, Croatia.

The computational analysis of the isomer- and conformer-dependent photochemistry of 1- and 2-naphthols and their microsolvated water clusters is motivated by their very different excited state reactivities. We present evidence that 1- and 2-naphthol follow distinct excited state deactivation pathways. The deactivation of 2-naphthols, 2-naphthol water clusters, as well as of the anti conformer of 1-naphthol is mediated by the optically dark πσ* state. The dynamics of the πσ* surface leads to the homolytic cleavage of the OH bond. On the contrary, the excited state deactivation of syn 1-naphthol and 1-naphthol water clusters follows an uncommon reaction pathway. Upon excitation to the bright ππ*(L ) state, a highly specific excited state hydrogen transfer (ESHT) to carbon atoms C8 and C5 takes place, yielding 1,8- and 1,5-naphthoquinone methides. The ESHT pathway arises from the intrinsic electronic properties of the ππ*(L ) state of 1-naphthols.
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http://dx.doi.org/10.1002/chem.201700691DOI Listing
June 2017

Photoinduced dynamics of formic acid monomers and dimers: the role of the double hydrogen bond.

J Phys Chem A 2012 Nov 10;116(46):11467-75. Epub 2012 Oct 10.

Rudjer Bošković Institute, 10000 Zagreb, Croatia.

Nonadiabatic dynamics in the framework of time-dependent density functional theory was used to simulate gas-phase relaxation dynamics of pairs of conformations of formic acid monomers (cis and trans FAM) and dimers (acyclic aFAD and cyclic cFAD). In the early phase of the excited state dynamics, elongation of the C═O bond and pyramidalization of the carbon atom is observed in both FAM and FAD. Subsequently, the photodynamics of FAM is shown to be dominated by fragmentation processes occurring mostly in the excited state and resulting in HCO and OH radicals. In only a few cases does the dissociation take place from the vibrationally excited ground electronic state, whereby CO and H(2)O are the major reaction products. In the dimers, single proton transfer triggers ultrafast relaxation to the ground electronic state. In the single hydrogen bonded dimer about half of the trajectories dissociate into electronically excited monomers, whereas this potentially destructive dissociation is effectively suppressed in the double hydrogen bonded dimer. Upon relaxation to the ground electronic state, separation of FAD into monomers takes place, but without their further fragmentation on the time scale of the simulation. We conclude that the crucial difference between the FAM and FAD photodynamics is that the latter is dominated by nondestructive radiationless deactivation pathways during which a key protective role is assumed by the single (aFAD) or double (cFAD) intermonomer hydrogen bonds.
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http://dx.doi.org/10.1021/jp3074865DOI Listing
November 2012