Binding Free Energy Research Articles

A Computational Study of the siRNA-Silica Nanoparticle Binding Process.

Molecular dynamics simulations were performed to investigate the structural and energetic features related to the direct binding of a short interfering RNA (siRNA) molecule on a silica nanoparticle functionalized with 3-aminopropyltriethoxysilane (APTES) groups, immersed in a sodium chloride aqueous solution at physiological concentration. Three different grafting densities of APTES were evaluated, namely, 2.7, 1.3, and 0.65 nm-2. Structural features as a function of the grafting density were analyzed and characterized in terms of density field profiles, pair correlation functions, and hydrogen bonding. The analysis of the orientation of siRNA during the binding process suggested that the oligonucleotide anchors to the surface by one of their ends in a tilted arrangement and subsequently, it rotates toward a surface-parallel stabilized configuration. Free energy of binding between siRNA and the silica nanoparticle was computed using the adaptive biasing force scheme. The results indicate that the binding process is essentially barrierless and consistent with a thermodynamically spontaneous reaction, yielding the largest binding free energy, of about ∼-36 kcal/mol at the largest APTES grafting density. However, a favorable binding was also observed at the lowest APTES density (∼-16 kcal/mol). a fact that would be advantageous to facilitate the further release of siRNA within the cell.

Identification of Potential Inhibitors of Histone Deacetylase 6 Through Virtual Screening and Molecular Dynamics Simulation Approach: Implications in Neurodegenerative Diseases

Background: Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. Methods: This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. Results: The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein–ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6–ligand complexes, confirming the stability of their interactions. Conclusions: The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

Host-Guest Binding Free Energies à la Carte: An Automated OneOPES Protocol.

Estimating absolute binding free energies from molecular simulations is a key step in computer-aided drug design pipelines, but the agreement between computational results and experiments is still very inconsistent. Both the accuracy of the computational model and the quality of the statistical sampling contribute to this discrepancy, yet disentangling the two remains a challenge. In this study, we present an automated protocol based on OneOPES, an enhanced sampling method that exploits replica exchange and can accelerate several collective variables to address the sampling problem. We apply this protocol to 37 host-guest systems. The simplicity of setting up the simulations and producing well-converged binding free energy estimates without the need to optimize simulation parameters provides a reliable solution to the sampling problem. This, in turn, allows for a systematic force field comparison and ranking according to the correlation between simulations and experiments, which can inform the selection of an appropriate model. The protocol can be readily adapted to test more force field combinations and study more complex protein-ligand systems, where the choice of an appropriate physical model is often based on heuristic considerations rather than systematic optimization.

BEGAN: Boltzmann-Reweighted Data Augmentation for Enhanced GAN-Based Molecule Design in Insect Pheromone Receptors.

Identifying small molecules that bind strongly to target proteins in rational molecular design is crucial. Machine learning techniques, such as generative adversarial networks (GAN), are now essential tools for generating such molecules. In this study, we present an enhanced method for molecule generation using objective-reinforced GANs. Specifically, we introduce BEGAN (Boltzmann-enhanced GAN), a novel approach that adjusts molecule occurrence frequencies during training based on the Boltzmann distribution exp(-ΔU/τ), where ΔU represents the estimated binding free energy derived from docking algorithms and τ is a temperature-related scaling hyperparameter. This Boltzmann reweighting process shifts the generation process toward molecules with higher binding affinities, allowing the GAN to explore molecular spaces with superior binding properties. The reweighting process can also be refined through multiple iterations without altering the overall distribution shape. To validate our approach, we apply it to the design of sex pheromone analogs targeting Spodoptera frugiperda pheromone receptor SfruOR16, illustrating that the Boltzmann reweighting significantly increases the likelihood of generating promising sex pheromone analogs with improved binding affinities to SfruOR16, further supported by atomistic molecular dynamics simulations. Furthermore, we conduct a comprehensive investigation into parameter dependencies and propose a reasonable range for the hyperparameter τ. Our method offers a promising approach for optimizing molecular generation for enhanced protein binding, potentially increasing the efficiency of molecular discovery pipelines.

Discovery of α-amylase and α-glucosidase dual inhibitors from NPASS database for management of Type 2 Diabetes Mellitus: A chemoinformatic approach.

Postprandial hyperglycemia, typical manifestation of Type 2 Diabetes Mellitus (T2DM), is associated with notable global morbidity and mortality. Preventing the advancement of this condition by delaying the rate of glucose absorption through inhibition of α-amylase and α-glucosidase enzymatic activities is of utmost importance. Finding a safe antidiabetic drug is essential since those that are currently on the market have drawbacks like unpleasant side effects. The current study utilized computer-aided drug design (CADD), as a quick and affordable method to find a substitute drug template that can be used to control postprandial hyperglycemia by modulating the activity of α-amylase and α-glucosidase enzymes. The Natural Products Activity and Species database (NPASS) (30,926 compounds) was screened in silico, with a focus on evaluating drug-likeness, toxicity profiles and ability to bind on a target protein. Two molecules NPC204580 (Chrotacumine C) and NPC137813 (1-O-(2-Methoxy-4-Acetylphenyl)-6-O-(E-Cinnamoyl)-Beta-D-Glucopyranoside) were identified as potential dual inhibitors for α-amylase and α-glucosidase with free binding energies of -14.46 kcal/mol and -12.58 kcal/mol for α-amylase, and -8.42 kcal/mol and -8.76 kcal/mol for α-glucosidase, respectively. The molecules showed ionic, H-bonding and hydrophobic interactions with critical amino acid residues of both enzymes. Moreover, 100 ns molecular dynamic simulations showed that both molecules are stable on the receptors' active sites based on root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the Generalized Born surface area (GBSA) energy calculated. The two compounds are thus promising therapeutic agents for T2DM that merit further investigation due to their excellent binding energies, encouraging pharmacokinetics, toxicity profiles, and stability as demonstrated in simulated studies.

Insilico discovery of novel Phosphodiesterase 4 (PDE4) inhibitors for the treatment of psoriasis: Insights from computer aided drug design approaches.

Psoriasis is chronic immune-mediated inflammatory disorder characterized by various comorbidities, erythematous plaques with silvery scale which can lead to psoriatic arthritis. The phosphodiesterase 4 (PDE4) protein is a potential drug target to control Psoriasis. In the current study, pharmacophore-based virtual screening of Diversity library of ChemDiv database was first performed, and then the screened hits were docked to the active site of PDE4 to choose the best binding modes. Forty-six hits generated during the virtual screening were prepared and docked to the PDE4 receptor by SP docking module of glide. The binding affinities of the selected hits were calculated by molecular docking and based on the affinities, ten hits were selected for the bioactivity scores prediction and ADMET analysis. Based on the ADMET profiling, four hits D356-2630, C700-2058, G842-0420 and F403-0203 were processed to MD simulations for stability analysis. The outcomes showed that these compounds showed strong binding with proteins with better binding free energies. Based on the results of our study, we proposed that these hits can function as lead in the biological assays and in vitro studies are required to develop the novel drug candidates.

Activating Oxygen via the 3‐Electron Pathway to Hydroxyl Radical by La‐O4 Single‐atom on WO3 for Water Purification

Shifting photocatalytic oxygen activation towards 3‐electron (e‐) pathway to hydroxyl radicals, instead of the normal 1 e‐ to superoxide radicals, becomes increasingly important for pollution degradation since hydroxyl radicals possess a high oxidation potential (2.80 V). Here, we demonstrate a selective oxygen activation to hydroxyl radicals via 3 e‐ pathway using single atomically dispersed La based on WO3 fabricated with oxygen vacancies to weaken La‐O coordination strength (denoted as LaO4‐WOv). Unsaturated‐state La overcomes the rate‐limited step of 2 e‐ oxygen reduction reaction towards to hydrogen peroxide via tuning binding free energy of key reaction intermediate *OOH, stepped by easy generation of hydroxyl radicals via 1 e‐. This strategy alters the activation of oxygen process from 1 e‐ to 3 e‐. Hydrogen peroxide and hydroxyl radicals over LaO4‐WOv produces 3.8 and 3.3 mmol L‐1 h‐1, 35 and 8 times that of detected over WO3, respectively. Rapid and complete removal of tetracycline realizes over LaO4‐WOv with 0.077 min‐1 of rate constant, 38 times that of WO3. Degradation efficiencies keep greater than 98% following five repeats, revealing a practical‐utilization‐level robust stability. This work builds an unsaturated‐state transition metal site for manipulating oxygen activation towards an effective water purification as a representative application.

In silico studies on nicotinamide analogs as competitive inhibitors of nicotinamidase in methicillin-resistant Staphylococcus aureus.

Nicotinamidase/PncA is a member of the hydrolase enzyme family, catalyzing the de-amidation of nicotinamide (NM) to nicotinic acid (NA) via salvage pathway. Products are fed into Preiss-Handler pathway for NAD+ biosynthesis which is an important enzyme cofactor and crucial for redox balance in microorganisms. Pathogens like methicillin-resistant Staphylococcus aureus (MRSA) are NAD+ auxotroph and rely on their host environment for NAD+ precursors to synthesize NAD+. Mutations in nicotinamidase/PncA have been reported to be associated with resistance to pyrazinamide (PZA), a front-line anti-tubercular drug, underlying its importance as an important link in NAD+ biosynthesis network in pathogenic organisms such as MRSA. The conserved features of PncA and essentiality of salvage route in MRSA and the absence of this enzyme in humans and other eukaryotes are attractive options to explore therapeutics against this target. In this work, we have screened novel substrate analogs from the PubChem database using virtual screening approaches employing fingerprint tanimoto-based 2D similarity search against Staphylococcus aureus PncA (SaPncA). Identified compounds were further assessed using molecular dynamics simulations to investigate conformational stability and structural integrity. We propose two analogs, namely L28 and L33 with greater stability, favorable binding and strong binding free energies in MM-PBSA calculations. The strategy could provide an important clue in developing similar compound scaffolds as potent drug-like molecules against MRSA and other pathogenic species harboring this enzyme. Smaller scaffolds of these molecules could be attractive options for fragment-based derivatization for inhibitor discovery.

Activating Oxygen via the 3-Electron Pathway to Hydroxyl Radical by La-O4 Single-atom on WO3 for Water Purification.

Shifting photocatalytic oxygen activation towards 3-electron (e-) pathway to hydroxyl radicals, instead of the normal 1 e- to superoxide radicals, becomes increasingly important for pollution degradation since hydroxyl radicals possess a high oxidation potential (2.80 V). Here, we demonstrate a selective oxygen activation to hydroxyl radicals via 3 e- pathway using single atomically dispersed La based on WO3 fabricated with oxygen vacancies to weaken La-O coordination strength (denoted as LaO4-WOv). Unsaturated-state La overcomes the rate-limited step of 2 e- oxygen reduction reaction towards to hydrogen peroxide via tuning binding free energy of key reaction intermediate *OOH, stepped by easy generation of hydroxyl radicals via 1 e-. This strategy alters the activation of oxygen process from 1 e- to 3 e-. Hydrogen peroxide and hydroxyl radicals over LaO4-WOv produces 3.8 and 3.3 mmol L-1 h-1, 35 and 8 times that of detected over WO3, respectively. Rapid and complete removal of tetracycline realizes over LaO4-WOv with 0.077 min-1 of rate constant, 38 times that of WO3. Degradation efficiencies keep greater than 98% following five repeats, revealing a practical-utilization-level robust stability. This work builds an unsaturated-state transition metal site for manipulating oxygen activation towards an effective water purification as a representative application.

Anti-thrombotic Mechanisms of Echinochrome A on Arterial Thrombosis in Rats: In-Silico, In-Vitro and In-Vivo Studies.

Arterial thrombosis is one of the most significant healthcare concerns in the world. Echinochrome A (Ech-A) is a natural quinone pigment isolated from sea urchins. It has a variety of medicinal values associated with its antioxidant, anticancer, antiviral, anti-diabetic, and cardio-protective activities. The current study aims to investigate the effect and mechanism of Ech-A to inhibit thrombus formation induced by ferric chloride in rats. Twenty-four rats were assigned into four groups (n= 6); sham and thrombotic model groups were orally administered 2% DMSO, while the other groups were treated with two dosages of Ech-A (1 and 10 mg/kg, body weight). After seven days of administration, all groups were exposed to 50% ferric chloride for 10 min, except the sham group exposure to normal saline. The molecular docking showed the free binding energies of Ech-A and vitamin K (Vit. K) with Vit. K epoxide reductase were -8.5 and -9.8 kcal/mol, which confirm the antithrombotic activity of Ech-A. The oral administration of Ech-A caused a significant increase in partial thromboplastin time, prothrombin time, clotting time, platelet count, fibrinogen levels, factor VIII, glutathione reduced, catalase, nitric oxide, and glutathione S-transferase. While white blood cells count, calcium level, and malondialdehyde concentration significantly decreased. The histological examination revealed a definite improvement in the carotid and cardiac tissues in the Ech-A groups. The study results showed that Ech-A prevented thrombosis by several mechanisms, including chelating calcium ions, increasing the NO concentration, suppressing oxidative stress, and antagonizing Vit. K.

Identification of novel inhibitors targeting PI3Kα via ensemble-based virtual screening method, biological evaluation and molecular dynamics simulation.

PIK3CA gene encoding PI3K p110α is one of the most frequently mutated and overexpressed in majority of human cancers. Development of potent and selective novel inhibitors targeting PI3Kα was considered as the most promising approaches for cancer treatment. In this investigation, a virtual screening platform for PI3Kα inhibitors was established by employing machine learning methods, pharmacophore modeling, and molecular docking approaches. 28 potential PI3Kα inhibitors with different scaffolds were selected from the databases with 295,024 compounds. Among the 28 hits, hit15 exhibited the best inhibitory effect against PI3Kα with IC50 value less than 1.0µM. The molecular dynamics simulation indicated that hit15 could stably bind to the active site of PI3Kα, interact with some residues by hydrophobic, electrostatic and hydrogen bonding interactions, and finally induced PI3Kα active pocket substantial conformation changes. Stable H-bond interactions were formed between hit15 and residues of Lys776, Asp810 and Asp933. The binding free energy of PI3Kα-hit15 was -65.3kJ/mol. The free energy decomposition indicated that key residues of Asp805, Ile848 and Ile932 contributed stronger energies to the binding free energy. The above results indicated that hit15 with novel scaffold was a potent PI3Kα inhibitor and considered as a promisingcandidateforfurther drugdevelopment to treat various cancers with PI3Kα over activated.

A Comprehensive Evaluation of a Coumarin Derivative and Its Corresponding Palladium Complex as Potential Therapeutic Agents in the Treatment of Gynecological Cancers: Synthesis, Characterization, and Cytotoxicity

Background: The aim of this research is the synthesis and characterization of coumarin-palladium complex and the investigation of the cytotoxicity of both the ligand and the complex. Methods: The palladium( II) complex (CC) was obtained in the reaction between (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl-acetate (CL) and potassium-tetrachloropalladate(II) and characterized using IR and NMR spectra, experimentally and theoretically. Cytotoxicity of CL and CC were determined for human cervical carcinoma HeLa, ovarian cancer A2780, hormone dependent breast cancer MCF7, and colorectal cancer HCT116 lines. The interaction of investigated compounds with HSA was followed by spectrofluorimetric method. The binding mechanism in the active pocket was assessed via molecular docking simulations. Results: A low mean absolute error between experimental and theoretical data proved that the optimized structure corresponded to the experimental one. Both compounds showed a satisfactory selectivity index towards neoplastic cells. The binding affinity of tested compounds to the HSA were confirmed. The molecular docking showed a much lower change in the Gibbs free energy of binding for CC compared to CL. Conclusions: The obtained results revealed that CL and CC exhibit significant effects on several cancer cell lines and good binding properties to HSA, while molecular docking discovered that CC has the most pronounced activity against alpha-fetoprotein.

Spectroscopic, quantum computational, molecular dynamic simulations, and molecular docking investigation of the biologically important compound-2,6-diaminopyridine

To establish the role in future drug development, 2,6-diamino pyridine (2,6-DAP) was investigated experimentally using computational tools. NMR (1H,13C), FTIR, and UV–Vis spectra were analyzed for the titled compound. The molecular structure was optimized via DFT with the “B3LYP method with 6-311++G(d,p)” The optimized parameters of the structure were assessed with the observed bond characteristics. The vibrational frequencies were studied, PED was carried out, and the calculated vibrational frequency obtained was compared with the experimentally obtained FTIR. NMR (1H,13C) was calculated and compared with the experimentally obtained spectra. UV–vis spectra are calculated in the gaseous phase and different mediums of solvents (methanol, DMSO) by employing the PCM solvent model and TD-DFT method, and the estimated value was compared with experimentally measured data. NBO analysis was done to study the donor-acceptor interaction. The extent of electron charge transfer inside the molecular structure was examined using HOMO–LUMO energy values. The study of excitation analysis led to the creation of E.D.D and H.D.D maps in methanol and DMSO. The AIM and ELF analysis was employed to compute the iso-surface projections, ellipticity, and binding energies. The MEP and Fukui functions evaluate the molecule’s reactive zones. Hirshfeld research was done to analyze interactions among the molecules in the structure of the crystal, and 3D Hirshfeld tops and 2D fingerprint layouts were developed. The molecular docking procedure was used, followed by a 100 ns MD simulation and computation of binding free energy found to delineate the binding affinity of the molecule toward human carbonic anhydrase II (HCA II). Molecular docking studies with several receptor proteins were also conducted to determine the most effective protein-ligand interactions. Biological assessments like drug-likeness also act upon the compound to verify the molecule’s drug-like nature.

New Indole-based Phenylthiazolyl-2,4-dihydropyrazolones as Tubulin polymerization inhibitors: Multicomponent synthesis, cytotoxicity evaluation, and in silico studies.

A facile multicomponent synthesis of new indole-based phenylthiazolyl-dihydropyrazolone hybrids, their structural characterization, biological evaluation, and in silico investigations as anticancer agents are reported. Lead molecule 5i of the series showed potent activity against MCF-7 breast cancer cells with an IC50 of 3.92± 0.01µM while showing minimal toxicity to normal human lung cells (IC50 = 69.85 ± 3.95 µM). Further studies show that the compound exhibits antiproliferative activity by inducing apoptosis in MCF-7 cancer cells. The wound healing assay indicated impaired cell migration under the concentration-dependent dosage. The lead molecule 5i also successfully inhibited the tubulin polymerase enzyme with an IC50 of 4.16 ± 0.18 µM. A flow cytometric assay indicated compound 5i induced apoptosis through G0 phase cell cycle arrest. The binding mode and interactions of the compound with the tubulin were predicted by molecular modelling and calculating binding free energies. These findings explain the current series as a new class of microtubule polymerization inhibitors with anticancer activity suitable for developing anticancer agents targeting tubulin.

Superimposing Ligands with a Ligand Overlay as an Alternate Topology Model for λ-Dynamics-Based Calculations.

Alchemical free energy (AFE) calculations can predict binding affinity changes as a function of structural modifications and have become powerful tools for lead optimization and drug discovery. Central to the setup and performance of AFE calculations is the manner of mapping alchemical transformations, known as the topology model. Single, dual, and hybrid topology models have been used with various AFE methods in the field. In recent works, λ-dynamics (λD) free energy calculations, specifically, have preferred the use of a hybrid multiple topology (HMT) for sampling multiple ligand perturbations. In this work, we evaluate a new topology method called ligand overlay (LO) for use with λD-based calculations, including the recently introduced λ-dynamics with a bias-updated Gibbs sampling (LaDyBUGS) approach. LO is a full multiple topology model that allows entire ligands to be sampled and restrained within a λ-dynamics framework. Relative binding free energies were computed with HMT or LO topology models with LaDyBUGS for 45 ligands across five protein benchmark systems. An overall Pearson R correlation of 0.98 and mean unsigned error of 0.32 kcal/mol were observed, suggesting that LO is a viable alternative topology model for λD-based calculations. We discuss the merits of using an HMT or LO model for future ligand studies with λD or LaDyBUGS calculations.

NOVEL HYBRIDS OF QUINOLINE LINKED PYRIMIDINE DERIVATIVES AS CYCLOOXYGENASE INHIBITORS: MOLECULAR DOCKING, ADMET STUDY, AND MD SIMULATION

Objective: Finding novel anti-inflammatory compounds is a crucial sector of research despite the significant advances this field has made. Inefficiency and unfavorable side effects are indeed potential drawbacks of conventional therapy utilizing steroidal or nonsteroidal drugs. This study aims to screen the designed quinoline-linked pyrimidine derivatives as Cyclooxygenase (COX) inhibitors. Methods: In the present study, we assessed the binding interactions of designed quinoline-linked pyrimidine derivatives with COX enzymes using a molecular docking approach. Using Molecular Dynamics (MD) simulations, the compound’s behavior was further investigated and its stability and conformational dynamics were demonstrated. Schrödinger's QikProp program was utilized to analyze the Absorption, Distribution, Metabolism, and Excretion (ADME) properties and toxicity properties were further investigated using Osiris Property Explorer. Additionally, the protein-ligand complexes' binding free energy has been ascertained using the Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) approach, which offered crucial information regarding the strength of their interactions. Results: The designed quinoline-linked pyrimidine derivatives fulfilled the Lipinski Rule of Five and had physicochemical characteristics within acceptable ranges, better ADME properties, and were non-toxic. Among the designed compounds, QPDU1 and QPDT6 showed correspondingly good docking scores for COX-1 and COX-2. QPDT6 was additionally analyzed by MD simulation studies to thoroughly examine the interaction between protein and ligand and their stability. Conclusion: The proposed compounds exhibit strong binding affinities to COX enzymes, stable interactions in MD simulations, and favorable drug-like features. These results support the need for more research and development of these substances as possible anti-inflammatory drugs.

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC50 = 0.0019 μM) and common mutant strains including K103 N (EC50 = 0.0019 μM), L100I (EC50 = 0.0087 μM), E138K (EC50 = 0.011 μM), along with low cytotoxicity and high selectivity index (CC50 = 21.95 μM, SI = 11478). Additionally, compound 3k demonstrated antiviral activity against HIV-2 with EC50 value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k could significantly inhibit the activity of HIV-1 reverse transcriptase (IC50 = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.

IDENTIFYING POTENTIAL hENR INHIBITORS AGAINST PROSTATE CANCER EMPLOYING IN SILICO DRUG REPURPOSING APPROACH

Objective: This study employed an in silico drug repurposing strategy to identify potential human enoyl acyl carrier protein reductase (hENR) inhibitors. Methods: The co-crystallized ligand triclosan was used as a reference standard. Initially, FDA-approved drugs from the Drug Bank database were docked against the hENR and compounds with appreciable binding affinities with the protein were shortlisted. The binding energy calculations, ADME analysis, and induced-fit docking results of shortlisted compounds led to the identification of two top hits, DB07676 and DB11399, which were further subjected to molecular dynamics simulation. Results: Of 2,509 ligands docked via High Throughput Virtual Screening (HTVS), the top 250 were assessed with Standard Precision (SP) and the top 25 with Extra Precision (XP) mode. Thirteen compounds were selected based on interactions and XP scores, ranging from-15.245 to-10.031. Relative binding free energies of ligands DB07676 and DB11399 were-54.18 and-61.38 kcalmol-1, respectively. ADME analysis confirmed that both ligands followed Lipinski's Rule, though DB11399 had a high log P, which could be addressed by adding polar groups. Induced Fit scores for DB07676 and DB11399 were-10.592 and-11.220, respectively. Molecular Dynamics simulations confirmed superior stability of these complexes with RMSD ranging from 1.2 to 3.5 Å for the protein and 1.7 to 5.2 Å for the ligand with DB07676-protein complex and 1.4 to 3.0 Å for the protein and 1.1 to 5.8 Å for the ligand with DB11399-protein complex. Conclusion: Our final findings suggested that DB07676 and DB11399 could be potential lead compounds as hENR inhibitors.

Discovering Lassa virus nucleoprotein inhibitors via in silico drug repositioning approach

Lassa fever, caused by the zoonotic Lassa virus (LASV), poses a significant health threat in Africa, leading to thousands of infections and deaths annually and has the potential to spread to other parts of the world. Despite the urgency for effective treatments, there are currently no approved drugs or vaccines for Lassa fever. LASV possesses a unique negative-sense RNA genome, and NP plays a crucial role in viral assembly and infection. Crystallographic analysis reveals distinct domains in NP, with the N-terminal domain involved in RNA binding and the C-terminal domain exhibiting exoribonuclease activity, suppressing type I interferon-mediated immune responses. This study explores the potential of repurposing existing FDA-approved drugs by targeting the N-terminal domain of LASV’s nucleoprotein (NP). Docking simulations and molecular dynamics experiments were conducted, revealing promising interactions between NP and widely used and well tolerated drugs such as metacycline, eltrombopag, glimepiride, lurasidone, paliperidone, prednisone, doxazosin, flavin mononucleotide, and pimozide. These drugs exhibited stable binding throughout 100 ns simulations, with interactions resembling those observed with the natural ligand, dTTP. Binding free energy calculations identified key amino acids, particularly Phe176 and Arg300, as crucial for drug-NP interactions. Notably, drugs like FMN, prednisone, metacycline, pimozide, and glimepiride displayed binding affinities comparable to dTTP, suggesting their potential as LASV inhibitors. The study underscores the importance of further experimental and clinical validation of these in silico findings. The identified drugs present promising candidates for potential treatments for Lassa fever, addressing the current gap in approved therapeutics for this life-threatening infectious disease.

An integrated bioinformatics approach to early diagnosis, prognosis and therapeutics of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is one of the most deadly tumors characterized by poor survival rates. Advances in therapeutics and precise identification of biomarkers can potentially reduce the mortality rate. Thus, this study aimed to identify a set of common and stable gene biomarkers through integrated bioinformatics approaches that might be effective for NSCLC early diagnosis, prognosis, and therapies. Four gene expression profiles (GSE19804, GSE19188, GSE10072, and GSE32863) downloaded from the Gene Expression Omnibus database to identify common differential expressed genes (DEGs). A total of 213 overlapping DEGs (oDEGs) between NSCLC and healthy samples were identified by using statistical LIMMA method. Then 6 common top-ranked key genes (KGs) (CENPF, CAV1, ASPM, CCNB2, PRC1, and KIAA0101) were selected by using four network-measurer methods in the protein– protein interaction network. The GO functional and KEGG pathway enrichment analysis were performed to reveal some significant functions and pathways associated with NSCLC progression. Transcriptional and post-transcriptional factors of KGs were identified through the regulatory interaction network. The prognostic power and expression level of KGs were validated by using the independent data through the Kaplan–Meier and Box plots, respectively. Finally, 4 KGs–guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC.