Molecular Mechanics Poisson-Boltzmann Surface Area Research Articles

Molecular docking and dynamics simulation study of quinones and pyrones from Alternaria solani and Alternaria alternata with HSP90: an important therapeutic target of cancer

Although cancer continues to be one of the world’s major causes of death, current cancer drugs have many serious side effects. There remains a need for new anticancer agents to overcome these shortcomings. Alternaria is one of the most widespread fungal genera, many species of which produce several classes of metabolites with potential polypharmacological activities. A few quinones and pyrones from Alternaria spp. have proven to exert cytotoxic effects against certain cancer cell lines, but their molecular mode of action is not known. The current study aimed to investigate the potential mechanisms that underlie the anticancer activity of a few selected quinones and pyrones from Alternaria solani and Alternaria alternata by molecular docking and dynamic simulation approaches. The selected metabolites were screened for their binding affinity to Heat shock protein 90 (HSP90), which is a known anticancer drug target. Molecular docking studies have revealed that Macrosporin, Altersolanol B, Fonsecin, and Neoaltenuene have good binding affinities with the target protein and the stabilities of the formed complexes were evaluated through molecular dynamics simulations. By analyzing the Root Mean Square Distance (RMSD), Root Mean Square Fluctuation (RMSF), and Principal Component Analysis (PCA) plots obtained from molecular dynamics simulations, this study shows that the complexes of all 4 lead molecules with target protein are stable over a 100 ns period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were used to compute the binding free energies. The lead molecules were studied using in-silico analysis to determine their drug-likeness based on their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and physicochemical properties. The results demonstrate that Macrosporin, Fonsecin, and Neoaltenuene could become promising anticancer molecules that target HSP90. Communicated by Ramaswamy H. Sarma

Fibroblast growth factor 5 (FGF5) and its missense mutant FGF5-H174 underlying trichomegaly: a molecular dynamics simulation investigation

The missense mutation Y174H of FGF5 (FGF5-H174) had been associated with trichomegaly, characterized by abnormally long and pigmented eyelashes. The amino acid tyrosine (Tyr/Y) at position 174 is conserved across many species, proposedly holding important characteristics for the functions of FGF5. Microsecond molecular dynamics simulations along with protein-protein docking and residue interacting network analysis were employed to investigate the structural dynamics and binding mode of both wild-type (FGF5-WT) and its mutated counterpart (FGF5-H174). It was found that the mutation decreased number of hydrogen bonds within the protein, sheet secondary structure, interaction of residue 174 with other residues, and number of salt-bridges. On the other hand, the mutation increased solvent accessible surface area, number of hydrogen bonds between the protein and solvent, coil secondary structure, protein C-alpha backbone root mean square deviation, protein residue root mean square fluctuations, as well as occupied conformational space. In addition, protein-protein docking integrated with molecular dynamics simulations and molecular mechanics - Poisson-Boltzmann surface area (MM/PBSA) binding energy calculation demonstrated that the mutated variant possessed stronger binding affinity towards fibroblast growth factor receptor 1 (FGFR1). However, residue interaction network analysis demonstrated that the binding mode of the FGFR1-FGF5-H174 complex was drastically different from that of the FGFR1-FGF5-WT complex. In conclusion, the missense mutation conferred more instability within itself and stronger binding affinity towards FGFR1 with distinctively altered binding mode or residue connectivity. These findings might help explain the decreased pharmacological activity of FGF5-H174 towards FGFR1, underlying trichomegaly. Communicated by Ramaswamy H. Sarma

Development and test of highly accurate endpoint free energy methods. 2: Prediction of logarithm of n-octanol-water partition coefficient (logP) for druglike molecules using MM-PBSA method.

The logarithm of n-octanol-water partition coefficient (logP) is frequently used as an indicator of lipophilicity in drug discovery, which has substantial impacts on the absorption, distribution, metabolism, excretion, and toxicity of a drug candidate. Considering that the experimental measurement of the property is costly and time-consuming, it is of great importance to develop reliable prediction models for logP. In this study, we developed a transfer free energy-based logP prediction model-FElogP. FElogP is based on the simple principle that logP is determined by the free energy change of transferring a molecule from water to n-octanol. The underlying physical method to calculate transfer free energy is the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA), thus this method is named as free energy-based logP (FElogP). The superiority of FElogP model was validated by a large set of 707 structurally diverse molecules in the ZINC database for which the measurement was of high quality. Encouragingly, FElogP outperformed several commonly-used QSPR or machine learning-based logP models, as well as some continuum solvation model-based methods. The root-mean-square error (RMSE) and Pearson correlation coefficient(R) between the predicted and measured values are 0.91 log units and 0.71, respectively, while the runner-up, the logP model implemented in OpenBabel had an RMSE of 1.13 log units and R of 0.67. Given the fact that FElogP was not parameterized against experimental logP directly, its excellent performance is likely to be expanded to arbitrary organic molecules covered by the general AMBER force fields.

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling.

The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort to find new leads. The study combined In silico and in vitro approaches to identify novel potential synthetic small-molecule inhibitors targeting the Leishmania donovani sterol methyltransferase (LdSMT). The LdSMT enzyme in the ergosterol biosynthetic pathway is required for the parasite's membrane fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of LdSMT homologue in the human host and its conserved nature among all Leishmania parasites makes it a viable target for future antileishmanial drugs. Initially, six known inhibitors of LdSMT with IC50 < 10 μM were used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled three-dimensional structure of LdSMT using AutoDock Vina. Consequently, nine compounds with binding energies ranging from -7.5 to -8.7 kcal/mol were identified as potential hit molecules. Three compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of -8.7, -8.2, and -8.0 kcal/mol, lower than 22,26-azasterol (-7.6 kcal/mol), a known LdSMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and molecular mechanics Poisson-Boltzmann surface area calculations showed that the residues Asp25 and Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of the three hits was evaluated in vitro against the promastigotes of L. donovani, mean half-maximal inhibitory concentrations (IC50) of 21.9 ± 1.5 μM (STOCK6S-06707), 23.5 ± 1.1 μM (STOCK6S-84928), and 118.3 ± 5.8 μM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920 inhibited the growth of Trypanosoma brucei, with IC50 of 14.3 ± 2.0 μM and 18.1 ± 1.4 μM, respectively. The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.

Repurposing of phyto-ligand molecules from the honey bee products for Alzheimer's disease as novel inhibitors of BACE-1: small molecule bioinformatics strategies as amyloid-based therapy.

Alzheimer's disease (AD) is one of the neurodegenerative diseases, manifesting dementia, spatial disorientation, language, cognitive, and functional impairment, mainly affects the elderly population with a growing concern about the financial burden on society. Repurposing can improve the traditional progress of drug design applications and could speed up the identification of innovative remedies for AD. The pursuit of potent anti-BACE-1 drugs for AD treatment has become a pot boiler topic in the recent past and to instigate the design of novel improved inhibitors from the bee products. Drug-likeness characteristics (ADMET: absorption, distribution, metabolism, excretion, and toxicity), docking (AutoDock Vina), simulation (GROMACS), and free energy interaction (MM-PBSA, molecular mechanics Poisson-Boltzmann surface area) analyses were performed to identify the lead candidates from the bee products (500 bioactives from the honey, royal jelly, propolis, bee bread, bee wax, and bee venom) for Alzheimer's disease as novel inhibitors of BACE-1 (beta-site amyloid precursor protein cleaving enzyme (1) receptor using appropriate bioinformatics tools. Forty-four bioactive lead compounds were screened from the bee products through high throughput virtual screening on the basis of their pharmacokinetic and pharmacodynamics characteristics, showing favorable intestinal and oral absorption, bioavailability, blood brain barrier penetration, less skin permeability, and no inhibition of cytochrome P450 inhibitors. The docking score of the forty-four ligand molecules was found to be between -4 and -10.3 kcal/mol, respectively, exhibiting strong binding affinity to BACE1 receptor. The highest binding affinity was observed in the rutin (-10.3 kcal/mol), 3,4-dicaffeoylquinic acid (-9.5 kcal/mol), nemorosone (-9.5 kcal/mol), and luteolin (-8.9 kcal/mol). Furthermore, these compounds demonstrated high total binding energy -73.20 to -105.85 kJ/mol), and low root mean square deviation (0.194-0.202 nm), root mean square fluctuation (0.0985-0.1136 nm), radius of gyration (2.12 nm), number of H-bonds (0.778-5.436), and eigenvector values (2.39-3.54 nm2) in the molecular dynamic simulation, signifying restricted motion of Cα atoms, proper folding and flexibility, and highly stable with compact of the BACE1 receptor with the ligands. Docking and simulation studies concluded that rutin, 3,4-dicaffeoylquinic acid, nemorosone, and luteolin are plausibly used as novel inhibitors of BACE1 to combat AD, but further in-depth experimental investigations are warranted to prove these in silico findings.

Interaction of Some Asymmetrical Porphyrins with U937 Cell Membranes-In Vitro and In Silico Studies.

The aim of the present study was to assess the effects exerted in vitro by three asymmetrical porphyrins (5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin, 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatozinc(II), and 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatocopper(II)) on the transmembrane potential and the membrane anisotropy of U937 cell lines, using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH), respectively, as fluorescent probes for fluorescence spectrophotometry. The results indicate the hyperpolarizing effect of porphyrins in the concentration range of 0.5, 5, and 50 μM on the membrane of human U937 monocytic cells. Moreover, the tested porphyrins were shown to increase membrane anisotropy. Altogether, the results evidence the interaction of asymmetrical porphyrins with the membrane of U937 cells, with potential consequences on cellular homeostasis. Molecular docking simulations, and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy of binding calculations, supported the hypothesis that the investigated porphyrinic compounds could potentially bind to membrane proteins, with a critical role in regulating the transmembrane potential. Thus, both the free base porphyrins and the metalloporphyrins could bind to the SERCA2b (sarco/endoplasmic reticulum ATPase isoform 2b) calcium pump, while the metal complexes may specifically interact and modulate calcium-dependent (large conductance calcium-activated potassium channel, Slo1/KCa1.1), and ATP-sensitive (KATP), potassium channels. Further studies are required to investigate these interactions and their impact on cellular homeostasis and functionality.

Folic acid functionalized carbon nanotubes as pH controlled carriers of fluorouracil: Molecular dynamics simulations

This study deals with molecular dynamics simulations of the folic acid (FA) functionalized carbon nanotube (CNT) as a pH-responsive carrier of fluorouracil (5-FU) drug. We chose FA as a targeting agent, as the folate receptor is considerably upregulated by a broad spectrum of cancer cells. Thus, it may facilitate the targeted delivery of chemotherapeutic agents. The results showed that the FA does not affect the loading capacity of CNT at neutral pH so both CNT and CNTFA can load 51 drug molecules. Unmodified CNT behaves in the same manner at different pH conditions, and so cannot be used as a pH-selective nanocarrier. However, the maximum loading capacity of CNTFA is decreased to 45 by decreasing the environmental pH. The molecular mechanics Poisson-Boltzmann surface area analysis showed that the hydrophobic and π-π stacking interactions are the main forces behind the complex stability. The least value of △Gbind belongs to the CNTFA:5-FU at low pH, which is favorable for drug release from a thermochemical viewpoint. The lowest and highest values of diffusion coefficients are those of CNTFA:5-FU at neutral and low pH, respectively. This means that CNTFA holds the drug molecules tightly at physiological pH, but releases them at low pH environments. Also, the reduction of the number of hydrogen bonds between CNTFA and 5-FU molecules as well as a decrease in height of the radial distribution function profile at low pH propose the CNTFA as a pH-sensitive nanocarrier for 5-FU. The simulation results show the important effect of the FA on the controlled release of 5-FU from CNT, which is suitable for targeted drug delivery applications.

Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I.

The monkeypox outbreak has become a global public health emergency. The lack of valid and safe medicine is a crucial obstacle hindering the extermination of orthopoxvirus infections. The identification of potential inhibitors from natural products, including Traditional Chinese Medicine (TCM), by molecular modeling could expand the arsenal of antiviral chemotherapeutic agents. Monkeypox DNA topoisomerase I (TOP1) is a highly conserved viral DNA repair enzyme with a small size and low homology to human proteins. The protein model of viral DNA TOP1 was obtained by homology modeling. The reliability of the TOP1 model was validated by analyzing its Ramachandran plot and by determining the compatibility of the 3D model with its sequence using the Verify 3D and PROCHECK services. In order to identify potential inhibitors of TOP1, an integrated library of 4103 natural products was screened via Glide docking. Surface Plasmon Resonance (SPR) was further implemented to assay the complex binding affinity. Molecular dynamics simulations (100 ns) were combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations to reveal the binding mechanisms of the complex. As a result, three natural compounds were highlighted as potential inhibitors via docking-based virtual screening. Rosmarinic acid, myricitrin, quercitrin, and ofloxacin can bind TOP1 with KD values of 2.16 μM, 3.54 μM, 4.77 μM, and 5.46 μM, respectively, indicating a good inhibitory effect against MPXV. The MM/PBSA calculations revealed that rosmarinic acid had the lowest binding free energy at -16.18 kcal/mol. Myricitrin had a binding free energy of -13.87 kcal/mol, quercitrin had a binding free energy of -9.40 kcal/mol, and ofloxacin had a binding free energy of -9.64 kcal/mol. The outputs (RMSD/RMSF/Rg/SASA) also indicated that the systems were well-behaved towards the complex. The selected compounds formed several key hydrogen bonds with TOP1 residues (TYR274, LYS167, GLY132, LYS133, etc.) via the binding mode analysis. TYR274 was predicted to be a pivotal residue for compound interactions in the binding pocket of TOP1. The results of the enrichment analyses illustrated the potential pharmacological networks of rosmarinic acid. The molecular modeling approach may be acceptable for the identification and design of novel poxvirus inhibitors; however, further studies are warranted to evaluate their therapeutic potential.

The Structural Basis of African Swine Fever Virus pS273R Protease Binding to E64 through Molecular Dynamics Simulations.

Identification of novel drugs for anti-African swine fever (ASF) applications is of utmost urgency, as it negatively affects pig farming and no effective vaccine or treatment is currently available. African swine fever virus (ASFV) encoded pS273R is a cysteine protease that plays an important role in virus replication. E64, acting as an inhibitor of cysteine protease, has been established as exerting an inhibitory effect on pS273R. In order to obtain a better understanding of the interaction between E64 and pS273R, common docking, restriction docking, and covalent docking were employed to analyze the optimal bonding position between pS273R-E64 and its bonding strength. Additionally, three sets of 100 ns molecular dynamics simulations were conducted to examine the conformational dynamics of pS273R and the dynamic interaction of pS273R-E64, based on a variety of analytical methods including root mean square deviation (RMSD), root mean square fluctuation (RMSF), free energy of ligand (FEL), principal component analysis (PCA), and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis. The results show that E64 and pS273R exhibited close binding degrees at the activity center of ASFV pS273R protease. The data of these simulations indicate that binding of E64 to pS273R results in a reduction in flexibility, particularly in the ARM region, and a change in the conformational space of pS273R. Additionally, the ability of E64 to interact with polar amino acids such as ASN158, SER192, and GLN229, as well as charged amino acids such as LYS167 and HIS168, seems to be an important factor in its inhibitory effect. Finally, Octet biostratigraphy confirmed the binding of E64 and pS273R with a KD value of 903 uM. Overall, these findings could potentially be utilized in the development of novel inhibitors of pS273R to address the challenges posed by ASFV.

Simulations reveal molecular mechanisms of high affinity and selective binding of the tarantula venom protoxin-2 to the human NaV1.7 channel.

Human voltage-gated sodium channels (hNaV) are responsible for initiating and propagating action potentials in excitable cells and have been associated with numerous cardiac and neurological disorders. hNaV1.7 channels, present at the endings of pain-sensing nerves, have garnered a lot of scientific interest as potential targets for pain therapeutics by channel inhibition. Certain natural peptide toxins, such as the tarantula protoxin-2 (ProTx2), have high selectivity for hNaV1.7, and hence they serve as valuable scaffolds for peptide design in pain therapeutics. Here, we present the mechanisms by which ProTx2 can bind and modulate hNaV1.7 channel gating kinetics. Using Rosetta biomolecular modeling software, we constructed atomistic structural models of the hNaV1.7 Voltage-Sensing Domain (VSD) 2 and 4 in the activated and deactivated states. Then, we docked ProTx2 onto the VSDs, embedded the structures into lipid bilayers solvated by aqueous NaCl solution, and performed microsecond-long all-atom molecular dynamics (MD) simulations of those systems using the CHARMM36m force field and Amber PMEMD software. Afterward, we performed binding energetics analysis using molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations and conducted Brownian Dynamics simulations using BrownDye to calculate the second-order association rate constants. Our analysis revealed numerous important inter-residue contacts that contribute to the toxin's high affinity for the channel. By understanding the various state- and subtype-specific mechanisms of toxin binding to the channel, we can develop strategies to improve the selectivity and potency of peptide toxins to create effective and safe pain therapeutics. In addition, the results could be incorporated into functional kinetic models to elucidate how ProTx2 can modulate electrical signal propagation in dorsal root ganglion neurons and thus pain sensing.

Molecular docking, 3D-QSAR and simulation studies for identifying pharmacophoric features of indole derivatives as 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) inhibitors

Excess of androgens leads to various diseases such as Poly-Cystic Ovarian Syndrome, Prostate Cancer, Hirsutism, Obesity and Acne. 17β-Hydroxysteroid Dehydrogenase type 5 (17β-HSD5) converts androstenedione into testosterone peripherally, thereby significantly contributing to the development of these diseases. Indole-bearing scaffolds are reported as potential 17β-HSD5 inhibitors for the manifestation of diseases arising due to androgen excess. In the present work, we have extensively performed a combination of molecular docking, Gaussian field-based 3D-QSAR, Pharmacophore mapping and MD-simulation studies (100 ns) to identify the pharmacophoric features of indole-based compounds as potent 17β-HSD5 inhibitors. Molecular simulation studies of the most potent compound in the binding pocket of enzyme revealed that the compound 11 was stable in the binding pocket and showed good binding affinity through interactions with various residues of active site pocket. The Molecular mechanics Generalized Born surface area continuum solvation (MM/GBSA) and Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations revealed that the compound 11 possessed a free binding energy of −36.36 kcal/mol and −7.00 kcal/mol, respectively, which was better as compared to reference compound Desmethyl indomethacin (DES). The developed pharmacophore will be helpful to design novel indole-based molecules as potent 17β-HSD5 inhibitors for the treatment of various androgenic disorders. Communicated by Ramaswamy H. Sarma

Discovery of Natural Bisbenzylisoquinoline Analogs from the Library of Thai Traditional Plants as SARS-CoV-2 3CLPro Inhibitors: In Silico Molecular Docking, Molecular Dynamics, and In Vitro Enzymatic Activity.

The emergence of SARS-CoV-2 in December 2019 has become a global issue due to the continuous upsurge in patients and the lack of drug efficacy for treatment. SARS-CoV-2 3CLPro is one of the most intriguing biomolecular targets among scientists worldwide for developing antiviral drugs due to its relevance in viral replication and transcription. Herein, we utilized computer-assisted drug screening to investigate 326 natural products from Thai traditional plants using structure-based virtual screening against SARS-CoV-2 3CLPro. Following the virtual screening, the top 15 compounds based on binding energy and their interactions with key amino acid Cys145 were obtained. Subsequently, they were further evaluated for protein-ligand complex stability via molecular dynamics simulation and binding free energy calculation using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches. Following drug-likeness and ADME/Tox assessments, seven bisbenzylisoquinolines were obtained, including neferine (3), liensinine (4), isoliensinine (5), dinklacorine (8), tiliacorinine (13), 2'-nortiliacorinine (14), and yanangcorinine (15). These compounds computationally showed a higher binding affinity than native N3 and GC-373 inhibitors and attained stable interactions on the active site of 3CLpro during 100 ns in molecular dynamics (MD) simulation. Moreover, the in vitro enzymatic assay showed that most bisbenzylisoquinolines could experimentally inhibit SARS-CoV-2 3CLPro. To our delight, isoliensinine (5) isolated from Nelumbo nucifera demonstrated the highest inhibition of protease activity with the IC50 value of 29.93 μM with low toxicity on Vero cells. Our findings suggested that bisbenzylisoquinoline scaffolds could be potentially used as an in vivo model for the development of effective anti-SARS-CoV-2 drugs.

Thyroid hormone transporters binding affinity of methoxypoly chlorinated biphenyls: Insights from molecular simulations and fluorescence competitive binding experiment

Triiodothyronine (T3) and thyroxine (T4) are essential for regulating cell metabolic rate and promoting the development and differentiation of brain tissue, especially in fetuses and newborns. In particular, it has been proved that MeO-PCBs have high binding to thyroid hormone transporters and can competitively bind to thyroid carrier proteins, thus destroying the transport of the thyroid hormone. Fluorescence competition binding experiments and docking results showed that the binding affinity decreased with the increase in number of chlorine atoms of MeO-PCBs. The interaction mechanism of MeO-PCBs with thyroid transporter (TTR) and thyroid binding globulin (TBG) was compared by computational simulation and the binding free energies were calculated by the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. Electrostatic potential analysis, Hirshfeld surface analysis and electron density difference maps confirmed the existence of electrostatic interactions. Secondly, noncovalent interaction (NCI) analysis further indicated that the main driving force for the combination of MeO-PCBs to TTR and TBG were electrostatic interaction and van der Waals interaction. The conformational changes of the protein after binding were studied by a molecular dynamic simulation.

Integrating microsecond timescale classical and biased molecular dynamics simulations to screen potential molecules for BRD4-BD1

Contemporary pre-clinical drug discovery is complemented by the combinatorial use of numerous computational techniques linked to computer-aided drug design and discovery. We combined inherently different computational analyses derived from multi-scale conventional, steered and umbrella sampling simulations to identify potential drug candidates for the first bromodomain of the human bromodomain containing protein 4 (BRD4-BD1). The BRD4-BD1 protein is a recognized therapeutic target for various diseases including cancer, neurological disorders, inflammation, and obesity. The in-house synthesized benzosuberene-sulfone (BSS) molecules were assessed for their potential to act as inhibitors against the BRD4-BD1 protein. We compared the molecular interactions and docking scores of BSS analogues with six different co-crystal inhibitors of the BRD4-BD1 protein. Further, the thermodynamic free energy of binding for each complex was estimated by the end-state Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) approach. Moreover, umbrella sampling simulations were utilized to validate the results obtained from MM/PBSA analyses and to demonstrate the unbinding/binding process of the most potent BSS analogue from the binding pocket of BRD4-BD1 protein. Our results show the potential of organosulfur molecules to be developed as inhibitors of the BRD4-BD1 protein and endorse their evaluation by suitable in-vitro and in-vivo studies.

In silico identification of potential PvFKBP35 inhibitors from Entadrophragma angolense Limonoids extracts as antimalarial agents

Plasmodium species, which are spread by female Anopheles mosquitoes, are responsible for malaria. Out of the five major Plasmodium species, Plasmodium falciparum and Plasmodium vivax are the most deadly and invasive species responsible for 99.7% and 75% of malaria cases in Africa and America respectively. Despite the invasive nature of malaria, the Plasmodium parasite continues to develop resistance to current drugs. It is therefore imperative to come up with new therapeutics to combat malaria. Previous studies have reported that Limonoids from the Meliaceae family possess antimalarial properties. This study therefore aims at employing computational approaches to identify potential antimalarial Limonoids by targeting PvFKBP35. PvFKBP35 has been reported to be a suitable target for antimalarial therapeutics as it is involved in various physiological activities including transcription, protein stability and folding. Molecular docking, Molecular Dynamics simulation and Molecular Mechanics-Poisson Boltzmann Surface Area calculation were employed to identify the potential leads. Sixteen [16] Limonoids extracted from the bark of the stem of Entadrophragma angolense were virtually screened against PvFKPB35. The top hit compounds were subjected to 500 ns Molecular Dynamics simulation and Molecular Mechanics – Poisson Boltzmann Surface Area calculations to examine their stability and free binding energy. Two potential leads, compounds 1 and 11 with binding energies −6.3 and −5.4 kcal/mol respectively were identified. The potential leads in complexed with PvFKBP35 had an average root mean square deviation of 1.18 ± 0.19 Å and 3.12 ± 0.60 Å, indicating their stability. Solvent Accessible Surface Area was utilized to predict the penetrative ability of the compounds into the binding pocket. Average Solvent Accessible Surface Area values of 327.88 ± 47.54 A2, 402.18 ± 39.81 A2 were obtained for compounds 1 and 11 respectively. ADMET estimations of compounds 1 and 11 predicted them to be druglike and do not violate Lipinski's rule of five. Compounds 1 and 11 need be tested in vitro to validate their antimalarial activity although they were predicted to be antiprotozoal with Pa values 0.207 and 0.162. These compounds can then serve as the scaffold for the design of novel antimalarial therapeutics.

Targeting Leishmania donovani sterol methyltransferase for leads using pharmacophore modeling and computational molecular mechanics studies

The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between −7 and −11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane permeability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.

Structural-Based Virtual Screening of FDA-Approved Drugs Repository for NSP16 Inhibitors, Essential for SARS-COV-2 Invasion Into Host Cells: Elucidation From MM/PBSA Calculation.

NSP16 is one of the structural proteins of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) necessary for its entrance to the host cells. It exhibits 2'O-methyl-transferase (2'O-MTase) activity of NSP16 using methyl group from S-adenosyl methionine (SAM) by methylating the 5-end of virally encoded mRNAs and shields viral RNA, and also controls its replication as well as infection. In the present study, we used in silico approaches of drug repurposing to target and inhibit the SAM binding site in NSP16 using Food and Drug Administration (FDA)-approved small molecules set from Drug Bank database. Among the 2 456 FDA-approved molecules, framycetin, paromomycin, and amikacin were found to be significant binders against the SAM binding cryptic pocket of NSP16 with docking score of -13.708, -14.997 and -15.841 kcal/mol, respectively. Classical molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculation depicted that all these three framycetin, paromomycin, and amikacin might be promising therapeutic leads towards SARS-CoV-2 infections via host immune escape inhibition pathway.

A molecular dynamics and quantum mechanical investigation of intermolecular interaction and electron-transfer mechanism between copper-containing nitrite reductase and redox partner pseudoazurin.

Much of biological electron transfer occurs between proteins. These molecular processes usually involve molecular recognition and intermolecular electron transfer (inter-ET). The inter-ET reaction between copper-containing nitrite reductase (CuNiR) and partner protein pseudoazurin (PAz) is the first step in denitrification, which is affected by intermolecular association. However, the transient interaction between CuNiR and PAz and the indistinct inter-ET pathway pose challenges for people to understand the biological functions of the CuNiR-PAz complex. Thus, molecular dynamics simulation and quantum mechanical calculation were used to investigate the question in this study. The interaction of the interface residues was determined through hydrogen bonds, root-mean-square deviation, root-mean-square fluctuation, the dynamics cross-correlation matrix, and molecular mechanics Poisson-Boltzmann surface area of molecular dynamics simulations. The interactions among the residues Glu89, Gly200, Asp205, Asn91, Glu204, Thr92, and Met141 on CuNiR and the residues Lys109, Ala15, Lys10, Asn9, Ile110, Met84, and Met16 on PAz are responsible for the stabilization of the complex. The binding free energy is up to -25.33 kcal mol-1. We compared the wild-type and mutant (M84A) interfacial optimized complex models at the CAM-B3LYP level with Grimme dispersion corrections (GD3) to confirm Met84 as a relay station for promoting the inter-ET. Additionally, to test whether Met84 may combine with the adjacent Met141 to form a special two-center, three-electron (S∴S)+ structure to promote the inter-ET, QM/MM was further performed to discuss the possibility of generating an electron stepping stone. Our study will promote a deep understanding of the stable protein-protein interaction, and the identified inter-residue interaction will be theoretical guidance for enhancing the catalytic activity of CuNiR in denitrification.

Bionics design of affinity peptide inhibitors for SARS-CoV-2 RBD to block SARS-CoV-2 RBD-ACE2 interactions

Coronavirus Disease 2019 (COVID-19), has already posed serious threats and impacts on the health of the population and the country's economy. Therefore, it is of great theoretical significance and practical application value to better understand the process of COVID-19 infection and develop effective therapeutic drugs. It is known that the receptor-binding structural domain (SARS-CoV-2 RBD) on the spike protein of the novel coronavirus directly mediates its interaction with the host receptor angiotensin-converting enzyme 2 (ACE2), and thus blocking SARS-CoV-2 RBD–ACE2 interaction is capable of inhibiting SARS-CoV-2 infection. Firstly, the interaction mechanism between SARS-CoV-2RBD-ACE2 was explored using molecular dynamics simulation (MD) coupled with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation method. The results of energy analysis showed that the key residues R403, R408, K417, and Y505 of SARS-CoV-2 RBD and the key residues D30, E37, D38, and Y41 of ACE2 were identified. Therefore, according to the hotspot residues of ACE2 and their distribution, a short peptide library of high-affinity SARS-CoV-2 RBD was constructed. And by using molecular docking virtual screening, six short peptides including DDFEDY, DEFEDY, DEYEDY, DFVEDY, DFHEDY, and DSFEDY with high affinity for SARS-CoV-2 RBD were identified. The results of MD simulation further confirmed that DDFEDY, DEYEDY, and DFVEDY are expected to be effective inhibitors. Finally, the allergenicity, toxicity and solubility properties of the three peptide inhibitors were validated.

Structure-based pharmacological screening, molecular docking and dynamic simulation reveals Dexketoprofen as a repurposable drug against Alzheimer's disease

Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that has a profound impact on memory, reasoning, learning, and organizational abilities. Acetylcholinesterase is one of the well-established targets for managing this disease. However, the existing acetylcholinesterase inhibitors are limited in many ways. Hence, in this study, we aimed to identify potential new drugs that can be repurposed to treat AD. For this purpose, an in silico screening of drug molecules that are structural analogues of the three FDA-approved acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine was performed, and 308 analogous compounds were recognized. To find the best possible drug repurposing candidates among them, an extremely rigorous filtering pipeline consisting of several drug-likeness parameters such as Lipinski, Ghose, Veber, Egan, Muegge, lead-likeness, and blood-brain barrier permeability was implemented. Finally, only 61 remained out of the 308 compounds. These 61 compounds then underwent molecular docking against the acetylcholinesterase receptor. Six compounds exhibited a higher binding affinity for the receptor compared to the FDA-approved drugs which were used as controls. Except for one compound that formed unfavorable molecular interactions, the rest were then subjected to sophisticated molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculation in order to evaluate their binding properties under a simulated physiological environment. Based on all the analyses, we are suggesting Dexketoprofen, a nonsteroidal anti-inflammatory drug as the most promising candidate for repurposing against AD. Our findings will pave the way for narrowing down the list of candidates to be tested in vitro and in vivo in further studies.