Drug-protein Complex Research Articles

The Role of Tryptophan in π Interactions in Proteins: An Experimental Approach.

In proteins, the amino acids Phe, Tyr, and especially Trp are frequently involved in π interactions such as π–π, cation−π, and CH−π bonds. These interactions are often crucial for protein structure and protein–ligand binding. A powerful means to study these interactions is progressive fluorination of these aromatic residues to modulate the electrostatic component of the interaction. However, to date no protein expression platform is available to produce milligram amounts of proteins labeled with such fluorinated amino acids. Here, we present a Lactococcus lactis Trp auxotroph-based expression system for efficient incorporation (≥95%) of mono-, di-, tri-, and tetrafluorinated, as well as a methylated Trp analog. As a model protein we have chosen LmrR, a dimeric multidrug transcriptional repressor protein from L. lactis. LmrR binds aromatic drugs, like daunomycin and riboflavin, between Trp96 and Trp96′ in the dimer interface. Progressive fluorination of Trp96 decreased the affinity for the drugs 6- to 70-fold, clearly establishing the importance of electrostatic π–π interactions for drug binding. Presteady state kinetic data of the LmrR–drug interaction support the enthalpic nature of the interaction, while high resolution crystal structures of the labeled protein–drug complexes provide for the first time a structural view of the progressive fluorination approach. The L. lactis expression system was also used to study the role of Trp68 in the binding of riboflavin by the membrane-bound riboflavin transport protein RibU from L. lactis. Progressive fluorination of Trp68 revealed a strong electrostatic component that contributed 15–20% to the total riboflavin-RibU binding energy.

Inside Back Cover: Mass Spectrometry Detection and Imaging of a Non‐Covalent Protein–Drug Complex in Tissue from Orally Dosed Rats (Angew. Chem. Int. Ed. 36/2022)

Flying elephants and delicate cargo: Electrospray ionization of proteins has been likened to making molecular elephants fly. Helen J. Cooper and co-workers (DOI: 10.1002/anie.202202075) demonstrate mass spectrometry detection and imaging of a non-covalent complex formed in vivo, comprising an endogenous protein and an exogenously administered drug molecule, directly from liver tissue. These methods will provide greater insight into protein–drug complexes in support of drug research and development.

Innenrücktitelbild: Mass Spectrometry Detection and Imaging of a Non‐Covalent Protein–Drug Complex in Tissue from Orally Dosed Rats (Angew. Chem. 36/2022)

Fliegende Elefanten und empfindliche Fracht. Die Elektrospray-Ionisierung von Proteinen wurde damit verglichen, molekulare Elefanten fliegen zu lassen. Helen J. Cooper und Mitarbeiter (e202202075) demonstrieren den massenspektrometrischen Nachweis und die Bildgebung eines in vivo erzeugten nicht-kovalenten Komplexes, der aus einem endogenen Protein und einem exogen verabreichten Wirkstoffmolekül besteht, direkt in Lebergewebe. Die Methode sollte bessere Einblicke in Protein-Wirkstoff-Komplexe zur Unterstützung der Wirkstoffentwicklung ermöglichen.

A comprehensive protein design protocol to identify resistance mutations and signatures of adaptation in pathogens.

Most pathogens mutate and evolve over time to escape immune and drug pressure. To achieve this, they alter specific hotspot residues in their intracellular proteins to render the targeted drug(s) ineffective and develop resistance. Such hotspot residues may be located as a cluster or uniformly as a signature of adaptation in a protein. Identifying the hotspots and signatures is extremely important to comprehensively understand the disease pathogenesis and rapidly develop next-generation therapeutics. As experimental methods are time-consuming and often cumbersome, there is a need to develop efficient computational protocols and adequately utilize them. To address this issue, we present a unique computational protein design protocol that identifies hotspot residues, resistance mutations and signatures of adaptation in a pathogen's protein against a bound drug. Using the protocol, the binding affinity between the designed mutants and drug is computed quickly, which offers predictions for comparison with biophysical experiments. The applicability and accuracy of the protocol are shown using case studies of a few protein-drug complexes. As a validation, resistance mutations in severe acute respiratory syndrome coronavirus 2 main protease (Mpro) against narlaprevir (an inhibitor of hepatitis C NS3/4A serine protease) are identified. Notably, a detailed methodology and description of the working principles of the protocol are presented. In conclusion, our protocol will assist in providing a first-hand explanation of adaptation, hotspot-residue variations and surveillance of evolving resistance mutations in a pathogenic protein.

Mass Spectrometry Detection and Imaging of a Non-Covalent Protein-Drug Complex in Tissue from Orally Dosed Rats.

Here, we demonstrate detection by mass spectrometry of an intact protein–drug complex directly from liver tissue from rats that had been orally dosed with the drug. The protein–drug complex comprised fatty acid binding protein 1, FABP1, non‐covalently bound to the small molecule therapeutic bezafibrate. Moreover, we demonstrate spatial mapping of the [FABP1+bezafibrate] complex across a thin section of liver by targeted mass spectrometry imaging. This work is the first demonstration of in situ mass spectrometry analysis of a non‐covalent protein–drug complex formed in vivo and has implications for early stage drug discovery by providing a route to target‐drug characterization directly from the physiological environment.

Mass Spectrometry Detection and Imaging of a Non-Covalent Protein-Drug Complex in Tissue from Orally Dosed Rats.

Here, we demonstrate detection by mass spectrometry of an intact protein-drug complex directly from liver tissue from rats that had been orally dosed with the drug. The protein-drug complex comprised fatty acid binding protein 1, FABP1, non-covalently bound to the small molecule therapeutic bezafibrate. Moreover, we demonstrate spatial mapping of the [FABP1+bezafibrate] complex across a thin section of liver by targeted mass spectrometry imaging. This work is the first demonstration of in situ mass spectrometry analysis of a non-covalent protein-drug complex formed in vivo and has implications for early stage drug discovery by providing a route to target-drug characterization directly from the physiological environment.

Systematic In Silico Studies of Corticosteroids and Its Binding Affinities with Glucocorticoid Receptor for Covid-19 Treatment: Ab-Initio, Molecular Docking and MD Simulation Studies

Corticosteroids are a form of medication that helps to reduce inflammation in the body. They also suppress the body immune system and are prescribed as medicines to treat diseases such as asthma, arthritis, lupus, and allergies because they reduce swelling, itching, redness, and allergic reactions. Further, corticosteroids have been recommended for use in different formulations and doses with varying durations in patients suffering with Covid-19 infection. In view of these facts, most commonly used corticosteroids namely, dexamethasone, prednisolone and hydrocortisone have been chosen in this study. Molecular geometries of these steroids have been optimized using density functional theory technique at B3LYP/6-31 + G(d,p) level. Further, optimized structures have been used for molecular docking that has been performed on SwissDock web server. The binding energies between corticosteroids and residues of the glucocorticoid receptor (1M2Z) represent that there exist several binding sites between drug molecules and residues of the target protein. Therefore, most preferred binding sites are taken for the molecular dynamics simulation which elucidates the stability of drug-protein complexes. Results have been used to discuss the binding affinities of dexamethasone, prednisolone and hydrocortisone with protein receptor along with various electronic properties of the corticosteroid drugs.

Identification of potential inhibitors against FemX of Staphylococcus aureus: A hierarchial in-silico drug repurposing approach

Staphylococcus aureus causes a wide range of common diseases in both community-acquired and hospital-acquired environments. The treatment becomes challenging due to the emergence of multi-drug resistant strains such as Methicillin-Resistant Staphylococcus aureus (MRSA). This study aims to find some drugs that can be used in repurposing. Virtual screening has been performed against S. aureus FemX using 1,918 FDA-approved drugs, which provides the top 10 drugs with good binding affinity. These drugs are re-docked to understand their interaction patterns with FemX. Docking study shows a high score for three drugs, Lumacaftor, Dihydroergocornine and Olaparib, and they are selected for molecular dynamics and quantum mechanical analysis. Molecular dynamics calculation shows that drug-FemX forms a stable structure compared to apo-FemX. Besides, the free energy landscape reveals that drug-protein complexes possess a single global minimum indicating their thermodynamic stability. MM/GBSA calculations show that Lumacaftor, Dihydroergocornine and Olaparib have the binding free energy of −30.03, −19.22 and −16.54 kcal/mol, respectively. The analysis of the wavefunctions from quantum chemical calculations reveals the presence of non-covalent interactions between drug and receptor, dominated by aromatic π-π interactions. The drug-receptor interaction energy estimated from quantum mechanical methods suggests an important role of dispersion interactions in stabilizing the drug molecules with FemX. The hierarchy of computational methods of increasing accuracy employed in this work finds Lumacaftor to be the most potent inhibitor against FemX.

Applying polypharmacology approach for drug repurposing for SARS-CoV2.

Exploring the new therapeutic indications of known drugs for treating COVID-19, popularly known as drug repurposing, is emerging as a pragmatic approach especially owing to the mounting pressure to control the pandemic. Targeting multiple targets with a single drug by employing drug repurposing known as the polypharmacology approach may be an optimised strategy for the development of effective therapeutics. In this study, virtual screening has been carried out on seven popular SARS-CoV-2 targets (3CLpro, PLpro, RdRp (NSP12), NSP13, NSP14, NSP15, and NSP16). A total of 4015 approved drugs were screened against these targets. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected based on the docking score, ability to interact with four or more targets and having a reasonably good number of interactions with key residues in the targets. The MD simulations and MM-PBSA studies showed reasonable stability of protein-drug complexes and sustainability of key interactions between the drugs with their respective targets throughout the course of MD simulations. The identified four drug molecules were also compared with the known drugs namely elbasvir and nafamostat. While the study has provided a detailed account of the chosen protein-drug complexes, it has explored the nature of seven important targets of SARS-CoV-2 by evaluating the protein-drug complexation process in great detail.Graphical abstractDrug repurposing strategy against SARS-CoV2 drug targets. Computational analysis was performed to identify repurposable approved drug candidates against SARS-CoV2 using approaches such as virtual screening, molecular dynamics simulation and MM-PBSA calculations. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected as potential candidates. Supplementary InformationThe online version contains supplementary material available at 10.1007/s12039-022-02046-0.

Computational prediction of the molecular mechanism of statin group of drugs against SARS-CoV-2 pathogenesis

Recently published clinical data from COVID-19 patients indicated that statin therapy is associated with a better clinical outcome and a significant reduction in the risk of mortality. In this study by computational analysis, we have aimed to predict the possible mechanism of the statin group of drugs by which they can inhibit SARS-CoV-2 pathogenesis. Blind docking of the critical structural and functional proteins of SARS-CoV-2 like RNA-dependent RNA polymerase, M-protease of 3-CL-Pro, Helicase, and the Spike proteins ( wild type and mutants from different VOCs) were performed using the Schrodinger docking tool. We observed that fluvastatin and pitavastatin showed fair, binding affinities to RNA polymerase and 3-CL-Pro, whereas fluvastatin showed the strongest binding affinity to the helicase. Fluvastatin also showed the highest affinity for the SpikeDelta and a fair docking score for other spike variants. Additionally, molecular dynamics simulation confirmed the formation of a stable drug-protein complex between Fluvastatin and target proteins. Thus our study shows that of all the statins, fluvastatin can bind to multiple target proteins of SARS-CoV-2, including the spike-mutant proteins. This property might contribute to the potent antiviral efficacy of this drug.

Is the Protein-Mediated Uptake of Drugs by Organic Anion Transporting Polypeptides a Real Phenomenon or an Artifact?

Plasma proteins or human serum albumin (HSA) have been reported to increase the in vitro intrinsic uptake clearance (CLint,uptake) of drugs by hepatocytes or organic anion transporting polypeptide (OATP)-transfected cell lines. This so-called protein-mediated uptake effect (PMUE) is thought to be due to an interaction between the drug-protein complex and the cell membrane causing an increase in the unbound drug concentration at the cell surface, resulting in an increase in the apparent CLint,uptake of the drug. To determine if the PMUE on OATP-mediated drug uptake is an artifact or a real phenomenon, we determined the effect of 1%, 2%, and 5% HSA on OATP1B1-mediated [human embryonic kidney (HEK)293 transfected cells] and passive CLint,uptake (mock HEK293 cells) on a cocktail of five statins. In addition, we determined the non-specific binding (NSB) of the statin-HSA complex to the cells/labware. The increase in uptake of atorvastatin, fluvastatin, and rosuvastatin in the presence of HSA was completely explained by the extent of NSB of the statin-HSA complex, indicating that the PMUE for these statins is an artifact. In contrast, this was not the case for OATP1B1-mediated uptake of pitavastatin and passive uptake of cerivastatin, suggesting that the PMUE is a real phenomenon for these drugs. Additionally, the PMUE on OATP1B1-mediated uptake of pitavastatin was confirmed by a decrease in its unbound IC50 in the presence of 5% HSA versus Hank's balanced salt solution buffer (HBSS). These data question the utility of routinely including plasma proteins or HSA in uptake experiments and the previous findings on PMUE on OATP-mediated drug uptake. SIGNIFICANCE STATEMENT: Here we report, for the first time, that the protein-mediated uptake effect (PMUE) on organic anion transporting polypeptide (OATP)-transported drugs could be an artifact of the non-specific binding (NSB) of the drug-albumin complex to cells/labware. Future experiments on PMUE must take into consideration such NSB. In addition, mechanisms other than PMUE need to be explored to explain the underprediction of in vivo OATP-mediated hepatic drug clearance from in vitro uptake studies.

Decomposing compounds enables reconstruction of interaction fingerprints for structure-based drug screening

BackgroundStructure-based drug repositioning has emerged as a promising alternative to conventional drug development. Regardless of the many success stories reported over the past years and the novel breakthroughs on the AI-based system AlphaFold for structure prediction, the availability of structural data for protein–drug complexes remains very limited. Whereas the chemical libraries contain millions of drug compounds, the vast majority of them do not have structures to crystallized targets,and it is, therefore, impossible to characterize their binding to targets from a structural view. However, the concept of building blocks offers a novel perspective on the structural problem. A drug compound is considered a complex of small chemical blocks or fragments, which confer the relevant properties to the drug and have a high proportion of functional groups involved in protein binding. Based on this, we propose a novel approach to expand the scope of structure-based repositioning approaches by transferring the structural knowledge from a fragment to a compound level.ResultsWe fragmented over 100,000 compounds in the Protein Data Bank (PDB) and characterized the structural binding mode of 153,000 fragments to their crystallized targets. Using the fragment’s data, we were able to artificially reconstruct the binding mode of over 7,800 complexes between ChEMBL compounds and their known targets, for which no structural data is available. We proved that the conserved binding tendency of fragments, when binding to the same targets, highly influences the drug’s binding specificity and carries the key information to reconstruct full drugs binding mode. Furthermore, our approach was able to reconstruct multiple compound-target pairs at optimal thresholds and high similarity to the actual binding mode.ConclusionsSuch reconstructions are of great value and benefit structure-based drug repositioning since they automatically enlarge the technique’s scope and allow exploring the so far ‘unexplored compounds’ from a structural perspective. In general, the transfer of structural information is a promising technique that could be applied to any chemical library, to any compound that has no crystal structure available in PDB, and even to transfer any other feature that may be relevant for the drug discovery process and that due to data limitations is not yet fully available. In that sense, the results of this work document the full potential of structure-based screening even beyond PDB.Graphical

Switching from ultrafast electron transfer to proton transfer in excited drug-protein complexes upon biotransformation.

Photosensitization by drugs is directly related with the excited species and the photoinduced processes arising from interaction with UVA light. In this context, the ability of gefitinib (GFT), a tyrosine kinase inhibitor (TKI) used for the treatment of a variety of cancers, to induce phototoxicity and photooxidation of proteins has recently been demonstrated. In principle, photodamage can be generated not only by a given drug but also by its photoactive metabolites that maintain the relevant chromophore. In the present work, a complete study of O-desmorpholinopropyl gefitinib (GFT-MB) has been performed by means of fluorescence and ultrafast transient absorption spectroscopies, in addition to molecular dynamics (MD) simulations. The photobehavior of the GFT-MB metabolite in solution is similar to that of GFT. However, when the drug or its metabolite are in a constrained environment, i.e. within a protein, their behavior and the photoinduced processes that arise from their interaction with UVA light are completely different. For GFT in complex with human serum albumin (HSA), locally excited (LE) singlet states are mainly formed; these species undergo photoinduced electron transfer with Tyr and Trp. By contrast, since GFT-MB is a phenol, excited state proton transfer (ESPT) to form phenolate-like excited species might become an alternative deactivation pathway. As a matter of fact, the protein-bound metabolite exhibits higher fluorescence yields and longer emission wavelengths and lifetimes than GFT@HSA. Ultrafast transient absorption measurements support direct ESPT deprotonation of LE states (rather than ICT), to form phenolate-like species. This is explained by MD simulations, which reveal a close interaction between the phenolic OH group of GFT-MB and Val116 within site 3 (subdomain IB) of HSA. The reported findings are relevant to understand the photosensitizing properties of TKIs and the role of biotransformation in this type of adverse side effects.

Subtractive proteomic analysis for identification of potential drug targets and vaccine candidates against Burkholderia pseudomallei K96243

Burkholderia pseudomallei is regarded as a global threat because of its ability to cause melioidosis, and potential as bioweapon. Intrinsic resistance to frontline antibiotics remains a major challenge in treating melioidosis. The increasing global burden of B. pseudomallei triggers the need to develop effective drugs and vaccine for controlling this pathogen. Therefore, we analyzed the whole proteome of B. pseudomallei K96243 using subtractive proteomic and immune-informatic analysis to find out potential drug target and vaccine candidate. Our analysis revealed 45 essential and non-homologous metabolic proteins, involved in different unique metabolic pathways. 36 out of 45 proteins can serve as novel drug targets and the remaining proteins had already been targeted with experimental drugs. 2 novel targets of cytoplasmic localization, namely dihydroneopterin aldolase and phosphoribosyl transferase were subjected to molecular docking with 14 antibiotics, which revealed the strong binding affinity of cefiderocol and tetracycline to the identified targets. Moreover, 100 ns molecular dynamic simulation and MM-PBSA calculation revealed the stability of drug-protein complexes. On the contrary, highly antigenic, non-allergic and non-toxic epitopes from three essential outer membrane proteins were joined by linkers and adjuvant to construct a chimeric peptide vaccine. The vaccine construct could efficiently bind to TLR-4 and generated robust immune response. The vaccine-receptor complex showed minimum deformability and good stability. Overall, our findings will aid in designing new inhibitors that disrupts the functionality of proposed targets and in the development of subunit vaccine for the therapeutic and prophylactic management of B. pseudomallei.

A Closer Look at Dexamethasone and the SARS-CoV-2-Induced Cytokine Storm: In Silico Insights of the First Life-Saving COVID-19 Drug.

The term cytokine storm refers to an uncontrolled overproduction of soluble inflammatory markers known as cytokines and chemokines. Autoimmune destruction of the lungs triggered by the release of these inflammatory markers often induces acute respiratory distress syndrome (ARDS). ARDS is an emergency condition with a high mortality rate in COVID-19 patients. Dexamethasone is the first repurposed corticosteroid with life-saving efficacy in patients with severe SARS-CoV-2 infection. Dexamethasone has traditionally been known to suppress the production of inflammatory markers at the transcriptional level, but its role as a direct therapeutic to neutralize cytokines, chemokines, their receptors, and functionally critical SARS-CoV-2 proteins has not yet been explored. Herein, we demonstrated that dexamethasone binds with high affinity to interlukin-1 (IL-1), IL-6, IL-8, IL-12, IL-21, INF2, TGFβ-1, INF-γ, CXCL8, some of the receptors, IL-1R, IL-21R, IFNGR, INFAR, IL-6αR-gp130, ST2 and the SARS-CoV-2 protein NSP macro X, and 3CLpro, forming stable drug–protein complexes. Our work implied that dexamethasone has the potential to directly neutralize inflammatory markers, further supporting its life-saving potential in patients with severe manifestations of COVID-19.

Computational insights into binding mechanism of drugs as potential inhibitors against SARS-CoV-2 targets.

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein–drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11696-021-01843-0.

Influence of Fluorine Substitution on Nonbonding Interactions in Selected Para-Halogeno Anilines.

A series of 4-halogeno aniline derivatives was studied employing combined theoretical and experimental methods (i. e. crystal structure analysis and vibrational spectroscopies). This simplified model system was selected to shed light on the impact of fluorine substitution on the formation of noncovalent interactions such as halogen bonds (XBs) and hydrogen bonds (HBs), which are key interactions in fluorinated/halogenated drug-protein complex formation. Comparative analysis of three previously reported and five newly determined crystal structures indicated that, in most cases, 2-fluoro and 2,6-difluoro substitution of 4-X anilines increases the ability of adjacent amine to form strong N-H⋅⋅⋅N HBs. Additionally, fluorine substituents in the difluorinated derivatives are competitive and attractive HB and XB acceptors and increase the probability of halogen-halogen contacts. A peculiar observation was made for 4-iodoaniline and 2,6-difluoro-4-iodoaniline, which form distinct interaction patterns compared to the corresponding 4-Cl and 4-Br analogs. The observed intramolecular N-H⋅⋅⋅F interactions lead to additional NH bands in the FT-IR spectra.

Effects of the Blending Ratio on the Design of Keratin/Poly(butylene succinate) Nanofibers for Drug Delivery Applications.

In recent years there has been a growing interest in the use of proteins as biocompatible and environmentally friendly biomolecules for the design of wound healing and drug delivery systems. Keratin is a fascinating protein, obtainable from several keratinous biomasses such as wool, hair or nails, with intrinsic bioactive properties including stimulatory effects on wound repair and excellent carrier capability. In this work keratin/poly(butylene succinate) blend solutions with functional properties tunable by manipulating the polymer blending ratios were prepared by using 1,1,1,3,3,3-hexafluoroisopropanol as common solvent. Afterwards, these solutions doped with rhodamine B (RhB), were electrospun into blend mats and the drug release mechanism and kinetics as a function of blend composition was studied, in order to understand the potential of such membranes as drug delivery systems. The electrophoresis analysis carried out on keratin revealed that the solvent used does not degrade the protein. Moreover, all the blend solutions showed a non-Newtonian behavior, among which the Keratin/PBS 70/30 and 30/70 ones showed an amplified orientation ability of the polymer chains when subjected to a shear stress. Therefore, the resulting nanofibers showed thinner mean diameters and narrower diameter distributions compared to the Keratin/PBS 50/50 blend solution. The thermal stability and the mechanical properties of the blend electrospun mats improved by increasing the PBS content. Finally, the RhB release rate increased by increasing the keratin content of the mats and the drug diffused as drug-protein complex.

Remdesivir analogs against SARS-CoV-2 RNA-dependent RNA polymerase

The COVID-19 pandemic has already taken many lives but is still continuing its spread and exerting jeopardizing effects. This study is aimed to find the most potent ligands from 703 analogs of remdesivir against RNA-dependent RNA polymerase (RdRp) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus . RdRp is a major part of a multi-subunit transcription complex of the virus, which is essential for viral replication. In clinical trials, it has been found that remdesivir is effective to inhibit viral replication in Ebola and in primary human lung cell cultures; it effectively impedes replication of a broad-spectrum pre-pandemic bat coronaviruses and epidemic human coronaviruses. After virtual screening, 30 most potent ligands and remdesivir were modified with triphosphate. Quantum mechanics-based quantitative structure–activity relationship envisages the binding energy for ligands applying partial least square (PLS) regression. PLS regression remarkably predicts the binding energy of the effective ligands with an accuracy of 80% compared to the value attained from molecular docking. Two ligands (L4:58059550 and L28:126719083), which have more interactions with the target protein than the other ligands including standard remdesivir triphosphate, were selected for further analysis. Molecular dynamics simulation is done to assess the stability and dynamic nature of the drug–protein complex. Binding-free energy results via PRODIGY server and molecular mechanics/Poisson-Boltzmann surface area method depict that the potential and solvation energies play a crucial role. Considering all computational analysis, we recommend the best remdesivir analogs can be utilized for efficacy test through in vitro and in vivo trials against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

In silico analysis of the antidiabetic terpenoid acankoreagenin binding to PPARγ.

Acankoreagenin (ACK) is a lupane triterpene found in several Acanthopanax and Schefflera plant species. ACK, also known as acankoreanogenin or HLEDA, bears a major structural analogy with other lupane triterpenoids such as impressic acid (IA) and the largely used phytochemical betulinic acid (BA). These compounds display marked anti-inflammatory, anti-diabetes, and anti-cancer properties. BA can form stable complexes with the peroxisome proliferator-activated receptor gamma (PPARγ). The tridimensional structure of the BA-PPARγ complex was used to perform a molecular docking analysis of the binding of ACK and IA to the protein. The 3-hydroxyl epimers (R/S) of each natural product were also modeled to examine the role of the C3-OH stereochemistry that distinguishes BA [3(S)] from ACK and AI [3(R)]. Calculations indicate that ACK can form more stable complexes with PPARγ than BA, upon insertion of the drug into the same binding pocket. The inversion of the C3-OH stereochemistry is not an obstacle for binding and the additional carboxy group of ACK at C23 position seems to reinforce the protein interaction. The 3-hydroxyl group does not play a major role in the geometry of the protein-drug complex, which is preserved between BA and ACK. Additional structure-binding relationships are provided, through the evaluation of the PPARγ binding capacity of ACK derivatives. Binding of ACK to PPARγ would account for its marked antidiabetic effect, at least partially. ACK can be used as a platform to design new antidiabetic compounds.