Molecular Modeling Methods Research Articles

Green synthesis, molecular structure, spectroscopic, ADME, DFT and molecular docking studies on methyl 10-trans,12-cis-octadecadienoate

The methyl 10-trans, 12-cis-octadecadienoate (MOD) obtained from the methanol extract of Calotropis gigantea flowers was studied using spectroscopic, computational molecular modelling and DFT methods in the current work. The Calotropis gigantea flowers were collected from the surroundings of Tamil Nadu, India's Thiruvallur district. The preparation for extraction of bioactive compound from Plant - based green synthesis of MOD from Calatropis gigantea. The FTIR spectra of MOD have been measured between in 400 and 4000 cm−1. Density functional theory is employed to determine the geometry of the molecules, vibrational frequencies and geometrical parameters by using B3LYP/6–311++G (d, p) basis set. The identification of the modes of vibration depended on the potential energy distributions (PEDs) which have been computed. The HOMO-LUMO energies, chemical hardness, and electro negativity of the molecule have been determined via the DFT/B3LYP/6–311++G (d, p) method. The intra molecular interactions and hydrogen bonding have been interpreted using natural bond orbital analysis by NBO 3.1 program. UV–Visible absorption spectra in the wavelength range of 200–400 nm was noticed, which indicates a molecular exchange of charges inside the molecule. The time dependent density functional theory (TD-DFT) method adopted for this study to determine the excited states of the title molecule. The Argus Lab application was implemented to evaluate the molecular docking tests that were conducted to look at the anti-cancer capabilities of the MOD molecule against Caspase 3.

Antimicrobial, Antidiabetic, Antioxidant, and Anticoagulant Activities of Cupressus sempervirens In Vitro and In Silico.

In the last decade, the urgent need to explore medicinal plants or drug development has increased enormously around the world to overcome numerous health problems. In the present investigation, HPLC indicated the existence of 18 phenolic and flavonoid compounds in the Cupressus sempervirens extract. Hesperetin represents the greatest concentration (25,579.57 µg/mL), while other compounds, such as pyro catechol, rutin, gallic acid, chlorogenic acid, naringenin, and quercetin, were recognized in concentrations of 2922.53 µg/mL, 1313.26 µg/mL, 1107.26 µg/mL, 389.09 µg/mL, 156.53 µg/mL, and 97.56 µg/mL, respectively. The well diffusion method documented the antibacterial/antifungal activity of C. sempervirens extract against E. faecalis, E. coli, C. albicans, S. typhi, S.aureus, and M. circinelloid with 35, 33, 32, 25, 23, and 21 mm inhibition zones, respectively, more than the standard antibiotic/antifungal agent. Low values ranging from 7.80 to 15.62 µg/mL of MIC and MBC were recorded for E. faecalis, E. coli, and C. albicans. From the 1- diphenyl-2-picryl hydrazyl (DPPH) assay, promising antioxidant activity was recorded for C. sempervirens extract with IC50 of an 8.97 µg/mL. Moreover, ferric reducing antioxidant power (FRAP) and total antioxidant capacity assays (TAC) confirmed the antioxidant activity of the extract, which was expressed as the ascorbic acid equivalent (AAE) of 366.9 ± 0.2 µg/mg and 102 ± 0.2 µg/mg of extracts, respectively. α-amylase and α-glucosidase inhibition % were determined to express the antidiabetic activity of the extract in vitro, with promising IC50 value (27.01 µg/mL) for α-amylase compared to that of acarbose (50.93 µg/mL), while IC50 value of the extract for α-glucosidase was 19.21µg/mL compared to that of acarbose 4.13 µg/mL. Prothrombin time (PT) and activated partial thromboplastin time (APTT) revealed the role of C. sempervirens extract as an anticoagulant agent if compared with the activity of heparin. Binding interactions of hesperetin and gallic acid were examined via the Molecular Operating Environment (MOE) Dock software against E. faecalis (PDB ID: 3CLQ), C. albicans (PDB ID: 7RJC), α-amylase (PDB ID: 4W93), and α-glucosidase (PDB ID: 3TOP). The obtained results shed light on how molecular modeling methods might inhibit the tested compounds, which have the potential to be useful in the treatment of target proteins.

BIOCATALYTIC CARBON DIOXIDE CAPTURE PROMOTED BY CARBONIC ANHYDRASE

The rapid and steady increase in the concentration of CO2, the most abundant greenhouse gas in the atmosphere, leads to extreme weather and climate events. Due to the burning of fossil fuels (oil, coal and natural gas), the concentration of CO2 in the air has been increasing in recent decades by more than 2 ppm per year, and in the last year alone - by 3.29 ppm. To prevent the "worst" scenarios of climate change, immediate and significant reductions in CO2 emissions through carbon management are needed. Aim. Analysis of the current state of research and prospects for the use of carbonic anhydrase in environmental decarbonization programs. Results. Carbonic anhydrase (CA) is an enzyme that accelerates the exchange of CO2 and HCO3 in solution by a factor of 104 to 106. To date, 7 types of CAs have been identified in different organisms. CA is required to provide a rapid supply of CO2 and HCO3 for various metabolic pathways in the body, explaining its multiple independent origins during evolution. Enzymes isolated from bacteria and mammalian tissues have been tested in CO2 sequestration projects using carbonic anhydrase (CA). The most studied is one of the isoforms of human KAz - hCAII - the most active natural enzyme. Its drawbacks have been instability over time, high sensitivity to temperature, low tolerance to contaminants such as sulphur compounds and the impossibility of reuse. Molecular modelling and enzyme immobilisation methods were used to overcome these limitations. Immobilisation was shown to provide greater thermal and storage stability and increased reusability. Conclusions. Capturing carbon dioxide using carbonic anhydrase (CA) is one of the most cost-effective methods to mitigate global warming, the development of which requires significant efforts to improve the stability and thermal stability of CAs.

Updating nucleosome positions within individual genes using molecular modeling methods and mnase sequencing data

Organization of chromatin plays an important role in regulating the genetic machinery of the cell. The basic unit of chromatin packaging is a nucleosome, which harbors DNA of about 145 base pairs in length. The packaging of genetic material and its accessibility to transcription enzymes and other regulatory chromatin proteins depends on the positions of nucleosomes. MNase sequencing is used to examine nucleosome positions in a genome. MNase sequencing data are sufficient for detecting the presence of nucleosomes on the sequence, but a determination of the precise locations of nucleosomes can be problematic. Accurate determination of nucleosome positions requires additional data filtering and processing. In this study, using MNase sequencing data, a combined method based on geometric analysis of nucleosome chain molecular models is proposed for selecting possible nucleosome positions. The developed algorithm efficiently eliminates inaccessible nucleosome chain combinations and conformationally prohibited nucleosome positions.

Development of an atomistic model of cement-incorporated nano-red mud material

The complexity of the hydration process of cementitious materials makes developing universal models that predict their mechanical behavior challenging. The current study used a novel molecular modeling method to develop a bottom-up model of the cement paste that incorporated different contents of the nano-red mud (nRM). A molecular dynamics (MD) simulation and dreiding force field were employed to build the ingredient-based models using the cement clinker phases and nRM oxides. Different cement-nRM mixtures were prepared and macroscopically tested under compression and flexure. In addition, a detailed microstructural analysis using XRD, SEM, EDS, and Raman was carried out on the prepared of nRM. The experimental results were used to validate the results of the developed molecular models. The simulation results demonstrated the capability of the atomistic models for predicting the strength and stiffness of the cement-nRM composites accurately. In addition, the developed hydrated cement model was found with the line of C–S–H-mineral structure (called tobermorite 11 Å). The molecular characterization, in terms of the radial distribution function and fractional free volume, also provided useful information on the local structures of the models. The molecular models of cement-nRM can be further used to predict the durability properties as well as gain deep insights into the mechanical performance of blended mixtures.

Refinement of Nucleosome Positions within Individual Genes Using Molecular Modeling Methods and MNase Sequencing Data

Refinement of Nucleosome Positions within Individual Genes Using Molecular Modeling Methods and MNase Sequencing Data

Structure-Dependent Mechanism of Organophosphate Release from Albumin and Butyrylcholinesterase Adducts When Exposed to Fluoride Ion: A Comprehensive In Silico Study.

The most favorable targets for retrospectively determining human exposure to organophosphorus pesticides, insecticides, retardants, and other industrial organophosphates (OPs) are adducts of OPs with blood plasma butyrylcholinesterase (BChE) and human serum albumin (HSA). One of the methods for determining OP exposure is the reactivation of modified BChE using a concentrated solution of KF in an acidic medium. It is known that under the action of fluoride ion, OPs or their fluoroanhydrides can be released not only from BChE adducts but also from the adducts with albumin; however, the contribution of albumin to the total pool of released OPs after plasma treatment with KF has not yet been studied. The efficiency of OP release can be affected by many factors associated with the experimental technique, but first, the structure of the adduct must be taken into account. We report a comparative analysis of the structure and conformation of organophosphorus adducts on HSA and BChE using molecular modeling methods and the mechanism of OP release after fluoride ion exposure. The conformational analysis of the organophosphorus adducts on HSA and BChE was performed, and the interaction of fluoride ions with modified proteins was studied by molecular dynamics simulation. The geometric and energy characteristics of the studied adducts and their complexes with fluoride ion were calculated using molecular mechanics and semiempirical approaches. The structural features of modified HSA and BChE that can affect the efficiency of OP release after fluoride ion exposure were revealed. Using the proposed approach, the expediency of using KF for establishing exposure to different OPs, depending on their structure, can be assessed.

Interaction of GHK Tripeptide with Receptors Targeted in Some Cancer Studies: A Theoretical Approach with Molecular Docking

Cancer, defined as the uncontrolled growth and proliferation of cells, is a serious disease seen in many people around the world. For this reason, a lot of work has been done and continues to be done by scientists for the diagnosis and treatment of cancer. It is known that various receptors are targeted in studies on cancers. In this study, ER, PR, EGFR and HER2 receptors, which are among the most frequently used target receptors, were selected. GHK is a tripeptide that has important benefits such as increasing cancer resistance and reversing cancer cells. In this study, the complex structures formed by the most commonly used target receptors (ER, PR, EGFR and HER2) and the GHK tripeptide were examined. These complex structures were obtained by molecular docking method that is a molecular modeling method used to predict how a receptor interacts with small molecules. As a result of the study, binding affinities, close interactions, and interaction types of GHK and receptors were determined, and interaction profiles with various drugs (such as tamoxifen, erlotinib and neratinib) in the literature were examined comparatively. In the light of the findings obtained in the studies, it was determined that the GHK tripeptide gave similar interaction profiles with the drugs used in cancer treatment.

Mechanistic investigation into the binding property of Yohimbe towards natural polymeric DNAs

DNA interactions with multivalent ligand(s) have increasingly become the subject of substantial research. For several small molecules with therapeutic potential, nucleic acids serve as their primary molecular target. Such interaction has been shown to affect transcription or replication, ultimately leading to apoptotic cell death. As a result, researchers are becoming increasingly interested in understanding how small molecules interact with DNA making it possible to develop new, DNA-specific drugs. The bioactive indole alkaloid, Yohimbe (Yohimbine; Yh) has been broadly studied in pharmacological properties while its binding mode to DNA has not been explicated so far. This study adopted molecular modelling and multi-spectroscopic methods to investigate the interaction between Yohimbine and herring testes (HT DNA) in physiological conditions. Minor hypochromic and bathochromic shifts of fluorescence intensity were observed, suggesting the binding of Yh to HT DNA. The Scatchard plot analyses using the McGhee-von Hipple method revealed non-cooperative binding and affinities in the range of 105 M−1. The thermodynamic parameters suggested exothermic binding, which was favoured by negative enthalpy and positive entropy changes from temperature-dependent fluorescence experiments. Salt-dependent fluorescence suggested that the interaction between the ligand and DNA was governed by non-polyelectrolytic forces. The results of iodide quenching, urea denaturation assay, dye displacement, and in silico molecular docking, suggested groove binding of Yh to HT DNA. Thus, the groove binding mechanism of interaction was validated by both biophysical and computational techniques. The structural elucidation and energetic profiling of Yh's interaction with naturally occurring polymeric DNA can be useful to the development of DNA-targeted therapeutics.

STRUCTURAL PREDICTION OF HUMAN ZIP 2 AND ZIP4 BASED ON HOMOLOGY MODELLING AND MOLECULAR SIMULATION

Objective: This study aimed to analyze the structural proteins of zinc transporters as the target for drug actions and their molecular interactions. Methods: The present study is about the homology modelling and analysis of the zinc transporter function using the in silico molecular modelling method. Homology modelling predicts the 3D structure of a protein based on the sequence alignment with one or more template proteins of known structure. This study using in silico molecular modelling method, explains the 3D structure of human ZIP 2 and ZIP4 with Ramachandran Plot analysis, physical and chemical characteristics, transmembrane prediction with structural biology, and binding site prediction through molecular docking simulation. Results: Based on the physicochemical properties of the 3D structure of the ZIP2 and ZIP4 proteins, each comprises 309 amino acids and 582 amino acids with pI values of 5.85 and 5.24. The amino acid composition analysis showed that both proteins contain many Leucine amino acids. The Ramachandran diagram concludes that both proteins are stable in the stereochemical conformation forming a secondary structure. The binding amino acids on ZIP2 include Glu281, His216, Ser284, and Arg46. The binding amino acids in ZIP4 include Gln148, Gln154, Thr155, His197, Ala138, and Lys157. Conclusion: Establishment of the structure and function of human ZIP2 and ZIP4 as zinc transporters in cell membranes and prediction of ZIP2 and ZIP4 binding sites through molecular dcoking.

Design of a structure-activity relationship model of vitamin K epoxide reductase (VKORC1) inhibitors combining chemical synthesis of new compounds, enzymatic assays and molecular modelling

Vitamin K antagonists (VKAs) anticoagulants have been used since the 1950s as medicines and rodenticides. These molecules are mainly 4-hydroxycoumarin derivatives and act by inhibiting the vitamin K epoxide reductase (VKORC1), an endoplasmic reticulum membrane resident enzyme. However, many VKORC1 mutations have been reported over the last decade, inducing VKAs resistances and thus treatments failures. Although studies have reported experimental and computational investigations of VKAs based on VKORC1 structural homology models, the development of new effective anticoagulants has been quite complex due to the lack of structural data and reliable structure–activity relationships. However, the recent publication of VKORC1 crystal structure provides new information for further studies. Based on these findings, we combined chemical synthesis, enzymatic assays and molecular modelling methods to design a structure–activity relationship (SAR) model. Our results proved that the lipophilicity, the membrane permeability of inhibitors and their affinity towards human VKORC1 enzyme are the main characteristics for potent anticoagulants. Our SAR model managed to rank compounds according to their ability to inhibit the human VKORC1. Such a tool might constitute an alternative to evaluate new molecules potency before their chemical synthesis and biological assessment and might assist the development of new VKAs.

Water-Aluminum Interaction as Driving Force of Linde Type A Aluminophosphate Hydration.

Linde type A (LTA) aluminophosphate is a promising candidate for an energy storage material used for low-temperature solar and waste-heat management. The mechanism of reversible water adsorption, which is the basis for potential industrial applications, is still not clear. In this paper, we provide mechanistic insight into various aspects of the hydration process using molecular modeling methods. Building on accurate DFT calculations and available experimental data, we first refine the existing empirical force-field used in subsequent classical molecular dynamics simulations that captures the relevant physics of the water binding process. We succeed in fully reproducing the experimentally determined X-ray structure factors and use them to estimate the number of water molecules present in the fully hydrated state of the material. Furthermore, we show that the translational and orientational mobility of the confined water is significantly reduced and resembles the dynamics of glassy systems.

Anticholinesterase and Serotoninergic Evaluation of Benzimidazole-Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease.

The etiology and pathogenesis of Alzheimer's disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1H-benzimidazol-2-ones with their potential molecular targets: cholinesterases (ChE) and three types of the Gs-protein-coupled serotonin receptors (5-HTR) 5-HT6, 5-HT4 and 5-HT7 (5-HT4R, 5-HT6R and 5-HT7R, respectively). A microplate modification of the Ellman method was used for the biochemical analysis of the inhibitory ability of the drugs towards ChE. Molecular modeling methods, such as molecular docking and molecular dynamics (MD) simulation in water and the lipid bilayer, were used to study the interaction of the compounds with ChE and 5-HTR. In vitro experiments showed that the tested compounds had moderate anticholinesterase activity. With the help of molecular modeling methods, the mechanism of interaction of the tested compounds with ChE was investigated, the binding sites were described and the structural features of the drugs that determine the strength of their anticholinesterase activity were revealed. Primary in silico evaluation showed that benzimidazole-carboxamides effectively bind to 5-HT4R and 5-HT7R. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride (compound 13) as the most promising for further experimental development.

Comprehensive insights into the binding of crystal violet and pepsin: Spectroscopic analysis, molecular model and biochemical method

As a well-known triphenylmethane dye, crystal violet (CV) has received extensive concerns owing to its harmful influence on human health. Pepsin is a digestive enzyme in the stomach that plays a crucial part in several physiological and pathological process. This research aimed to use spectroscopic experiments, computer simulation and enzyme activity assays to investigate the influence of CV on the functions and structure of pepsin from the perspective of binding. Fluorescence and UV–vis spectra confirmed the complex formation between CV and pepsin. Ka was in the order of 104 M−1, implying a moderate affinity between CV and pepsin. Multi non-covalent interactions played a crucial part in this binding process. The conformational alterations of pepsin caused by CV were reflected in β-sheet content reducing, and the presence of CV caused an activation of pepsin. The outcomes of molecular docking indicated that the interaction of Tyr75/Tyr189 with CV is the major cause for the fluorescence quenching phenomenon of pepsin. For molecular dynamics (MD) simulation, the CV-pepsin and free pepsin systems reached equilibrium in 40 ns. In addition, the compactness of pepsin changed after interacting with CV, which was in line with the results of solvent experiment. From the above results, CV has effects on the properties of pepsin, which may provide novel insights into the toxicological study of CV.

Molecular docking and biological activities of Ni(II), Cu(II) and Co(II) complexes with a new potentially hexadentate polyamine ligand; X-ray crystal structure of the Cu(II) complex

Three new metal complexes have been obtained from the reaction of a new polyamine (L) with Ni(II), Cu(II), and Co(II) ions. The X-ray structural analysis of the Cu(II) complex shows that the copper atom is in a very distorted square pyramidal environment, coordinated by five of the six nitrogen donor atoms of the potentially hexadentate ligand. To evaluate the biological potential of the ligand and the synthesized metal complexes, their binding behavior with DNA was studied by molecular modeling methods. The Molecular docking studies showed that the free ligand and its complexes were bound to the major groove of DNA. The antioxidant activities of the ligand and its metal complexes were also assessed, in vitro, using 2,2-diphenyl-1-picrylhydrazyl. The synthesized compounds were tested for activity against lung carcinoma epithelial cells (A549) using the MTT cell viability assay. A comparative study of the IC50 values indicated that the Cu(II) complex exhibited the highest activity, while the Co(II) and Ni(II) complexes showed more potent antiproliferative activity than the ligand. The antibacterial activities of the synthesized complexes were evaluated using micro-broth dilution and disk diffusion methods. The complexes showed greater antibacterial activity than the free ligand. Communicated by Ramaswamy H. Sarma

HydraMap v.2: Prediction of Hydration Sites and Desolvation Energy with Refined Statistical Potentials.

The complex network of water molecules within the binding pocket of a target protein undergoes alterations upon ligand binding, presenting a significant challenge for conventional molecular modeling methods to accurately characterize and compute the associated energy changes. We have previously developed an empirical method, HydraMap (J. Chem. Inf. Model. 2020, 60, 4359-4375), which employs statistical potentials to predict hydration sites and compute desolvation energy, achieving a reasonable balance between accuracy and speed. In this work, we present its improved version, namely, HydraMap v.2. We updated the statistical potentials for protein-water interactions through an analysis of 17 042 crystal protein structures. We also introduced a new feature to evaluate ligand-water interactions by incorporating statistical potentials derived from the solvated structures of 9878 small organic molecules produced by molecular dynamics simulations. By combining these potentials, HydraMap v.2 can predict and compare the hydration sites in a binding pocket before and after ligand binding, identifying key water molecules involved in the binding process, such as those forming bridging hydrogen bonds and unstable ones that can be replaced. We demonstrated the application of HydraMap v.2 in explaining the structure-activity relationship of a panel of MCL-1 inhibitors. The desolvation energies calculated by summing the energy change of each hydration site before and after ligand binding showed good correlation with known ligand binding affinities on six target proteins. In conclusion, HydraMap v.2 offers a cost-effective solution for estimating the desolvation energy during protein-ligand binding and also is practical in guiding lead optimization in structure-based drug discovery.

STOCHASTIC MODELING THE TRANSPORT COEFFICIENTS OF LIQUIDS

A method of stochastic molecular modeling (SMM) of liquid transport coefficients has been developed. They are calculated using fluctuation-dissipation theorems, but unlike the molecular dynamics (MD) method, the phase trajectories of the system are simulated stochastically. The force acting on the molecule is determined stochastically using the created database of intermolecular forces. The effectiveness of the method is demonstrated by the example of calculating transport coefficients. It is shown that the SMM method requires much less computational resources than the MD method.

Designing a Multi-Epitope Subunit Vaccine against VP1 Major Coat Protein of JC Polyomavirus.

The JC polyomavirus virus (JCPyV) affects more than 80% of the human population in their early life stage. It mainly affects immunocompromised individuals where virus replication in oligodendrocytes and astrocytes may lead to fatal progressive multifocal encephalopathy (PML). Virus protein 1 (VP1) is one of the major structural proteins of the viral capsid, responsible for keeping the virus alive in the gastrointestinal and urinary tracts. VP1 is often targeted for antiviral drug and vaccine development. Similarly, this study implied immune-informatics and molecular modeling methods to design a multi-epitope subunit vaccine targeting JCPyV. The VP1 protein epitopic sequences, which are highly conserved, were used to build the vaccine. This designed vaccine includes two adjuvants, five HTL epitopes, five CTL epitopes, and two BCL epitopes to stimulate cellular, humoral, and innate immune responses against the JCPyV. Furthermore, molecular dynamics simulation (100 ns) studies were used to examine the interaction and stability of the vaccine protein with TLR4. Trajectory analysis showed that the vaccine and TLR4 receptor form a stable complex. Overall, this study may contribute to the path of vaccine development against JCPyV.

Exploring molecular fingerprints of different drugs having bile interaction: a stepping stone towards better drug delivery.

Bile acids are amphiphilic substances produced naturally in humans. In the context of drug delivery and dosage form design, it is critical to understand whether a drug interacts with bile inside the gastrointestinal (GI) tract or not. This study focuses on the identification of structural fingerprints/features important for bile interaction. Molecular modelling methods such as Bayesian classification and recursive partitioning (RP) studies are executed to find important fingerprints/features for the bile interaction. For the Bayesian classification study, the ROC score of 0.837 and 0.950 are found for the training set and the test set compounds, respectively. The fluorine-containing aliphatic/aromatic group, the branched chain of the alkyl group containing hydroxyl moiety and the phenothiazine ring etc. are identified as good fingerprints having a positive contribution towards bile interactions, whereas, the bad fingerprints such as free carboxylate group, purine, and pyrimidine ring etc. have a negative contribution towards bile interactions. The best tree (tree ID: 1) from the RP study classifies the bile interacting or non-interacting compounds with a ROC score of 0.941 for the training and 0.875 for the test set. Additionally, SARpy and QSAR-Co analyses are also been performed to classify compounds as bile interacting/non-interacting. Moreover, forty-six recently FDA-approved drugs have been screened by the developed SARpy and QSAR-Co models to assess their bile interaction properties. Overall, this attempt may facilitate the researchers to identify bile interacting/non-interacting molecules in a faster way and help in the design of formulations and target-specific drug development.

Computational study of the binding orientation and affinity of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-1 considering the protein flexibility by using molecular dynamics and cross-docking.

The papain-like protease (PLpro) from zoonotic coronaviruses (CoVs) has been identified as a target with an essential role in viral respiratory diseases caused by Severe Acute Respiratory Syndrome-associated coronaviruses (SARS-CoVs). The design of PLpro inhibitors has been proposed as an alternative to developing potential drugs against this disease. In this work, 67 naphthalene-derived compounds as noncovalent PLpro inhibitors were studied using molecular modeling methods. Structural characteristics of the bioactive conformations of these inhibitors and their interactions at the SARS-CoV-1 PLpro binding site were reported here in detail, taking into account the flexibility of the protein residues. Firstly, a molecular docking protocol was used to obtain the orientations of the inhibitors. After this, the orientations were compared, and the recurrent interactions between the PLpro residues and ligand chemical groups were described (with LigRMSD and interaction fingerprints methods). In addition, efforts were made to find correlations between docking energy values and experimentally determined binding affinities. For this, the PLpro was sampled by using Gaussian Accelerated Molecular Dynamics (GaMD), generating multiple conformations of the binding site. Diverse protein conformations were selected and a cross-docking experiment was performed, yielding models of the 67 naphthalene-derived compounds adopting different binding modes. Representative complexes for each ligand were selected to obtain the highest correlation between docking energies and activities. A good correlation (R 2 = 0.948) was found when this flexible docking protocol was performed.