Molecular Mechanics Generalized Born Surface Area Research Articles

Revelation of potential drug targets of luteolin in Plasmodium falciparum through multi-target molecular dynamics simulation studies

In-silico techniques offer a fast, accurate, reliable, and economical approach to studying the molecular interactions between compounds and proteins. In this study, our main aim is to use in-silico techniques as a rational approach for the prediction of the molecular drug targets for luteolin against Plasmodium falciparum. Multi-target molecular docking, 100 nanoseconds (ns) molecular dynamics (MD) simulations, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations were carried out for luteolin against dihydrofolate reductase thymidylate synthase (PfDHFR-TS), dihydroorotate dehydrogenase (PfDHODH), and falcipain-2. The native ligands of each protein were used as a reference to evaluate the performance of luteolin. Luteolin outperformed the native ligands of all proteins at molecular docking and MD simulations studies. However, in the MM-GBSA calculations, luteolin outperformed the native ligand of only PfDHFR-TS but not PfDHODH and falcipain-2. Among the studied proteins, the in-silico approach predicted PfDHFR-TS as the most favorable drug target for luteolin. Communicated by Ramaswamy H. Sarma

13C NMR-based dereplication using MixONat software to decipher potent anti-cholinesterase compounds in Mesua lepidota bark

A bio-assay guided fractionation strategy based on cholinesterase assay combined with 13C NMR-based dereplication was used to identify active metabolites from the bark of Mesua lepidota. Eight compounds were identified with the aid of the 13C NMR-based dereplication software, MixONat, i.e., sitosterol (1), stigmasterol (2), α-amyrin (3), friedelin (6), 3β-friedelinol (7), betulinic acid (9), lepidotol A (10) and lepidotol B (11). Further bio-assay guided isolation of active compounds afforded one xanthone, pyranojacareubin (12) and six coumarins; lepidotol A (10), lepidotol B (11), lepidotol E (13), lepidotin A (14), and lepidotin B (15), including a new Mammea coumarin, lepidotin C (16). All the metabolites showed strong to moderate butyrylcholinesterase (BChE) inhibition. Lepidotin B (15) exhibited the most potent inhibition towards BChE with a mix-mode inhibition profile and a Ki value of 1.03 µM. Molecular docking and molecular dynamics simulations have revealed that lepidotin B (15) forms stable interactions with key residues within five critical regions of BChE. These regions encompass residues Asp70 and Tyr332, the acyl hydrophobic pocket marked by Leu286, the catalytic triad represented by Ser198 and His438, the oxyanion hole (OH) constituted by Gly116 and Gly117, and the choline binding site featuring Trp82. To gauge the binding strength of lepidotin B (15) and to pinpoint pivotal residues at the binding interface, free energy calculations were conducted using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) approach. This analysis not only predicted a favourable binding affinity for lepidotin B (15) but also facilitated the identification of significant residues crucial for the binding interaction.

Interactions and conformational changes of annexin A2/p11 heterotetramer models on a membrane: a molecular dynamics study

Ca2+-dependent membrane-binding by the Annexin A2/p11 heterotetramer (A2t) plays an important role in various biological processes including fibrinogen activation and exocytosis in neuroendocrine cells. Two models where A2t associates with a single membrane surface were generated and used to perform molecular dynamics simulations. The first model mimics initial A2t-membrane binding through both Annexin A2 (A2) subunits of A2t (TS model) while the second model mimics A2t-binding through a single A2 subunit (OS model). Conformational changes were summarized using principal component analysis (PCA), simulation snapshots, and distance plots from the simulations. The full TS model, including the p11 dimer, fully associates with the membrane adopting a stable structure with little conformational variation as evidence by PCA. The unassociated subunits of the OS model moved toward the membrane. The molecular mechanics/Generalized-Born surface area (MMGBSA) method was applied to investigate the energetics of the models. The MMGBSA results demonstrated that R63 of p11 was the primary contributor to the p11-membrane interaction. The TS model results were both consistent with those found in the literature and provide novel insights about the specific residues driving the A2t-membrane interaction. Additionally, it represents the most complete model of A2t on the membrane surface available. Communicated by Ramaswamy H. Sarma

Masoprocol: a promising candidate for targeting insulin resistance by inhibiting resistin with optimal druglikeness Potentials: an in silico approach

Resistin is a cysteine-rich secretory hormone that induces resistance to insulin, and its elevated expression is correlated with the onset of diabetes and several related metabolic disorders. Resistin performs its inhibitory role by connecting three identical subunits through Cys22-based disulfide linkages. The necessity to inhibit the formation of resistin trimer is one of the essential means to prevent the aggravation of diabetes mellitus type 2, obesity, and atherosclerosis. This study was conducted to screen the clinically approved drugs to find the most potent one to inhibit resistin with the best pharmacokinetics and drug-likeness properties. A total of 4654 clinically approved drugs were docked against the Cys22 residue of resistin. The top ten drugs with the highest high-precision (XP) docking scores were selected. Ioversol and masoprocol showed the highest XP docking and Molecular Mechanics-Generalized Born Surface Area (MMGBSA) scores, respectively, with double hydrogen bonding with the targeted Cys22. Molecular dynamics (MD) simulations showed that the masoprocol-resistin complex exhibited lower root mean square deviation (RMSD), radius of gyration, and root mean square fluctuation (RMSF) values than those observed in the ioversol-resistin complex. Both drugs induced drastic conformational changes in resistin monomer interactions. However, ioversol did not prove satisfying drug-likeness properties, while masoprocol showed the most favourable pharmacokinetic and drug-likeness properties. This study has demonstrated that masoprocol offers a novel inhibitory effect on resistin with the highest ligand affinity, making it a promising drug for combating insulin resistance. Communicated by Ramaswamy H. Sarma

In silico identification and analysis of potential inhibitors for acid phosphatase, HppA from Helicobacter pylori.

Helicobacter pylori is the most common cause of gastric ulcers and is associated with gastric cancer. The enzyme HppA of class C nonspecific acid phosphohydrolases (NSAPs) of H. pylori plays a crucial role in the electron transport chain. Herein, we report an in silico homology model of HppA consisting of a monomeric α + β model. A high throughput structure-based virtual screening approach yielded potential inhibitors against HppA with higher binding energies. Further analyses of molecular interaction maps and protein-ligand fingerprints, followed by molecular mechanics-generalized Born surface area (MM-GBSA) end point binding energy calculations of docked complexes, resulted in the detection of top binders/ligands. Our investigations identified potential substrate-competitive small molecule inhibitors of HppA, with admissible pharmacokinetic properties. These molecules may provide a starting point for developing novel therapeutic agents against H. pylori.

An integrative computational approach for the identification of dual inhibitors of isocitrate dehydrogenase 1 and 2 from phytocompounds of Phyllantus amarus

Genetic alterations of the genes encoding the isocitrate dehydrogenase (IDH) enzymes have been identified in about 20% of acute myeloid leukemia (AML) cases as well as many other forms of cancers. Notable among these alterations are the neomorphic IDH1_R132H and IDH2_R140Q mutations which lead to the production of an oncometabolite. Hence, their inhibition is widely considered a therapeutic strategy in the treatment of many cancers. While many inhibitors of the mutant enzymes have been developed, an inhibitor that is capable of co-inhibiting both enzymes are currently lacking while drug resistance has also limited the clinical usage of previously identified mono inhibitors. Consequently, this study employed molecular modeling approaches, such as molecular docking, molecular mechanics generalized Born Surface area (MM/GBSA), molecular dynamics (MD) simulation, and density functional theory (DFT) analysis to identify potential dual inhibitors of the previously mentioned mutant IDH1/2 from the phytocompounds of Phyllantus amarus. Of the 31 phytocompounds identified, 20 showed good binding affinities for both IDH1 _R132H and IDH2 _R140Q (ranging from −5.2 Kca/mol to −9.6 Kcal/mol) and had desirable pharmacokinetic properties. However, ellagic acid and pinoresinol possessed better pharmacokinetic properties, rendering suitable hits. Investigation of the behavior of the IDH1_R132H and IDH2_R140Q complexes with ellagic acid and pinoresinol via the RMSD, RMSF, and contact map analyses showed that all the complexes-maintained stability throughout the simulation time. Ultimately, ellagic acid and pinoresinol were identified as promising hits for the development of IDH1_R132H and IDH2_R140Q dual inhibitors. However, further experimental studies are needed to confirm their potential as therapies. Communicated by Ramaswamy H. Sarma

Marine-derived sea urchin compounds as potential anti-cancer drug candidate against colorectal cancer: In silico and in vitro studies

Sea urchin-derived compounds are potential candidates for the development of effective drugs for the treatment of cancer diseases. In this study, 19 compounds derived from sea urchin (Diadema savignyi) were used to treat colorectal cancer using the HCT116 cell line. However, molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamic (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) were used to confirm the ligand–protein interaction. Interactions of Importin-11 receptor with sea urchin compounds reveal that four compounds have higher binding affinities (ranging from -8.6 to -7.1 kcal/mol). In vitro testing revealed that the CID 6432458 compound was effective (docking score of −8.6 kcal/mol) against the HCT116 cell line. The cytotoxicity of HCT116 has been documented, with an IC50 value of 6.885 ± 4. MTT assay, apoptosis analysis, and cell cycle assay were utilized to examine cell death in colorectal cancer. In the MTT experiment, 15 µM and 20 µM dosages were associated with 77% cell death; however, flow cytometry analysis using the IC50 value revealed that the selected chemical induced greater apoptosis in the HCT116 cell line (58.5%). The gene expression data revealed that the apoptotic gene BAX is expressed at a higher level than the BCL-2 gene. The IPO11 gene was downregulated during treatment. In the experiment involving the cell cycle, the S phase for the 30 µM dose showed 75.1% apoptosis, which was greater than the other concentrations used alone. These in silico and in vitro analysis will not only provide new information about Importin-11 receptor and insight into colorectal cancer but will also facilitate the development of natural compounds in a significant and worthwhile manner.

Computer-aided drug design approaches applied to screen natural product’s structural analogs targeting arginase in Leishmania spp

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics–generalized Born surface area (MM–GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.

Exploring the Binding Mechanism of NRG1–ERBB3 Complex and Discovery of Potent Natural Products to Reduce Diabetes-Assisted Breast Cancer Progression

Diabetes mellitus significantly contributes to breast cancer progression, where hyperglycemia upregulates specific genes, leading to more aggressive tumor growth. In patients with BC that develop diabetes, neuregulin 1 (NRG1) and epidermal growth factor receptor 3 (ERBB3) overexpression exacerbate tumor growth and progression. Since the interaction between NRG1 and ERBB3 is critical for tumor growth, understanding the molecular mechanisms underlying NRG1–ERBB3 complex formation is essential for elucidating diabetes-assisted breast cancer progression. However, the key residues forming the NRG1–ERBB3 complex remain unknown. Here, we substituted specific residues in NRG1 with alanine and studied its interactions with ERBB3 using computational structural biology tools. We further screened the South African natural compounds database to target the complex’s interface residues to discover potential inhibitors. The conformational stability and dynamic features of NRG1–WT, –H2A, –L3A, and –K35A complexed with ERBB3 were subjected to 400 ns molecular dynamics simulations. The free binding energies of all NRG1–ERBB3 complexes were calculated using the molecular mechanics-generalized Born surface area (MM/GBSA). The H2 and L3 alanine substitutions caused a loss of interaction with ERBB3 residue D73, weakening the interaction with ERBB3. Screening 1300 natural compounds identified four (SANC00643, SANC00824, SANC00975, and SANC00335) with the best potential to inhibit ERRB3-NRG1 coupling. The binding free energies for each complex were − 48.55 kcal/mol for SANC00643, − 47.68 kcal/mol for SANC00824, − 46.04 kcal/mol for SANC00975, and − 45.29 kcal/mol for SANC00335, showing their overall stronger binding with ERBB3 than NRG1 and their potential to act as ERBB3-NRG1 complex inhibitors. In conclusion, this complex may represent a residue-specific drug target to inhibit BC progression.Graphical abstract

Multifunctional absorbents for oily pollution control and mechanistic insights with theoretical simulation

The fabrication of energy-efficient and high performing hydrophobic aerogels is highly desirable for addressing oil-based liquid pollution. The implementation of the aerogel adsorption process requires a comprehensive understanding of the macro-, micro-, and molecular-level mechanisms involved. To achieve this goal, molecular simulations can be employed to investigate the adsorption forces at the molecular level. Here, the cellulose extracted from Salvia miltiorrhiza Bunge residues (DS) were employed as natural building blocks to synthesize DS aerogel (DS-A) and subsequently silylated with methyltrimethoxysilane (MTMS). The resulting silylated DS aerogels (SDS-A) exhibited an exceptional adsorption capacity (25–105 g/g), endurable hydrophobicity, and a rapid oil adsorption rate of 5 s, with 2 wt% of DS cellulose (DS-C) and a porosity of 99.56%. Subsequently, the interactions were investigated between the silylated aerogel and oily liquids by means of docking, molecular dynamics (MD), and molecular mechanics-generalized Born surface area (MM-GBSA). Lipophilic energy and van der Waals energy surpassed Coulomb force in silylated cellulose/chlorobenzene complexes (−10.8 kcal/mol, −15.9 kcal/mol) and silylated cellulose/n-butyl acetate complexes (−4.3 kcal/mol, −17.1 kcal/mol). Molecular simulations revealed that van der Waals and hydrophobic interactions played crucial roles in adsorption. During the process, the adsorption mechanism was investigated at the molecular level, contributing to the understanding of silylated cellulose aerogel-based research. Moreover, the SDS-A demonstrated chemical durability with NaCl, NaOH, HCl, and oily liquids, as well as mechanical wear resistance without hydrophobic variation. Oil spill remediation results indicated that the aerogels could effectively facilitate continuous oil recycling from contaminated water in both artificial-driven and pump-driven experiments. This research provides novel insights into innovative solutions for oil-based liquid treatment technologies and future rational research.

Naringenin-4'-glucuronide as a new drug candidate against the COVID-19 Omicron variant: a study based on molecular docking, molecular dynamics, MM/PBSA and MM/GBSA

This study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (in silico). NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and −15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. In vitro and preclinical studies are needed to confirm these findings. Communicated by Ramaswamy H. Sarma

Modulatory properties of Thespesia garckeana (F. Hoffm.) Exell & Hillc. Aqueous fruit extract on female rats reproductive hormones and tissues histology and potential inhibitory activity of its constituents against SRD5α2

Ethnopharmacological relevanceThespesia garckeana (F. Hoffm.) Exell & Hillc. is called Gorontula (Kola of Tula) in Nigeria, Morojwa in Bostwana, and Thespesia garckeana in South Africa and is widely distributed across Africa. Its parts reportedly possess multiple medicinal properties and are employed for treating various diseases. In Tula, Gombe State, Nigeria, the ripe fruit decoction is taken as remedy for female infertility as documented by Ochokwu and co in the Journal of Biology, Agriculture and Healthcare in 2015. Aim of the studyThis research examined the effects of aqueous fruit extract of T. garckeana (F. Hoffm.) Exell & Hillc. (AFETG) on selected reproductive tissues and hormones in female rats and also evaluated the inhibitory potentials of its phytoconstituents against human 5-alpha reductase 2 (SRD5α2) using in silico approach. MethodsTwenty-five (25) sexually matured female rats were randomized into 5 groups (i.e. A - E). Oestrous in the rats was synchronized (subcutaneous oestradiol conjugate [10 μg/100 g BW]). Group A received distilled water (control). Group B received standard drug, clomiphene citrate (0.85 mg/kg BW), while groups C, D, and E received AFETG at 50, 100, and 200 mg/kg BW respectively. The animals were treated for five (5) days and sacrificed 24 h after. Their blood was collected and prepared for analysis of serum prolactin, oestradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) while ovaries, uteruses, and oviducts were studied for histological and histomorphometric changes. For the in silico study, the target protein, human steroid 5α-reductase 2 (SRD5α2) was prepared and its receptor grid was generated using Optimized Potential for Liquid Simulations-2005. The ligand 2D structures were prepared using LigPrep 2.4 software and docked using Glide. The binding energy of the ligands to the protein receptor was predicted using Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis. ResultsAFETG significantly increased serum levels of E2 but did not alter serum levels of prolactin, LH and FSH when compared with distilled water and clomiphene citrate. AFETG also significantly increased ovarian tertiary follicular diameter, oviductal epithelial height and serosa thickness as well as uterine endometrial epithelial height, endometrial thickness, and myometrial thickness when compared with control. Ovarian secondary follicular diameter and oviductal submucosa thickness and muscular thickness were significantly decreased by AFETG when compared with control. Two compounds in T. garckeana (F. Hoffm.) Exell & Hillc.; D-Melezitose (−12.55 kcal/mol XP GScore) and 1, 3, 4-trihydroxy-5-oxo cyclohexane-1-carboxylic acid (−9.136 kcal/mol XP GScore) exhibited higher binding affinities for SRD5α2 than the reference ligand, epristeride (−8.096 kcal/mol XP GScore).In conclusion, the ability of AFETG to increase serum E2 level, thickness of uterine endometrium and ovarian tertiary follicles size can be explored for the treatment of female infertility caused by thinning of the uterine endometrium and reduced follicular size. Two compounds in AFETG (i.e. D-Melezitose and 1, 3, 4-trihydroxy-5-oxo cyclohexane-1-carboxylic acid are potential inhibitors of SRD5α2, thus aiding the biosynthesis of E2. Available evidence therefore corroborate the traditional use of T. garckeana (F. Hoffm.) Exell & Hillc fruit as a female fertility enhancer in Northern Nigeria.

Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies.

β-amyloid cleaving enzyme 1 (BACE1) is regarded as an important target of drug design toward the treatment of Alzheimer's disease (AD). In this study, three separate molecular dynamics (MD) simulations and calculations of binding free energies were carried out to comparatively determine the identification mechanism of BACE1 for three inhibitors, 60W, 954 and 60X. The analyses of MD trajectories indicated that the presence of three inhibitors influences the structural stability, flexibility and internal dynamics of BACE1. Binding free energies calculated by using solvated interaction energy (SIE) and molecular mechanics generalized Born surface area (MM-GBSA) methods reveal that the hydrophobic interactions provide decisive forces for inhibitor-BACE1 binding. The calculations of residue-based free energy decomposition suggest that the sidechains of residues L91, D93, S96, V130, Q134, W137, F169 and I179 play key roles in inhibitor-BACE1 binding, which provides a direction for future drug design toward the treatment of AD.

Binding Mechanism of Inhibitors to Heat Shock Protein 90 Investigated by Multiple Independent Molecular Dynamics Simulations and Prediction of Binding Free Energy.

The heat shock protein (HSP90) has been an import target of drug design in the treatment of human disease. An exploration of the conformational changes in HSP90 can provide useful information for the development of efficient inhibitors targeting HSP90. In this work, multiple independent all-atom molecular dynamics (AAMD) simulations followed by calculations of the molecular mechanics generalized Born surface area (MM-GBSA) were performed to explore the binding mechanism of three inhibitors (W8Y, W8V, and W8S) to HSP90. The dynamics analyses verified that the presence of inhibitors impacts the structural flexibility, correlated movements, and dynamics behavior of HSP90. The results of the MM-GBSA calculations suggest that the selection of GB models and empirical parameters has important influences on the predicted results and verify that van der Waals interactions are the main forces that determine inhibitor-HSP90 binding. The contributions of separate residues to the inhibitor-HSP90 binding process indicate that hydrogen-bonding interactions (HBIs) and hydrophobic interactions play important roles in HSP90-inhibitor identifications. Moreover, residues L34, N37, D40, A41, D79, I82, G83, M84, F124, and T171 are recognized as hot spots of inhibitor-HSP90 binding and provide significant target sites of for the design of drugs related to HSP90. This study aims to contribute to the development of efficient inhibitors that target HSP90 by providing an energy-based and theoretical foundation.

Identifying USP1 Inhibitors with Allosteric Effect on Its Triple Catalytic Center through Virtual Screening

Previous studies have shown that downregulation of ubiquitin-specific protease 1 (USP1) can inhibit cell proliferation and promote apoptosis, indicating that targeting USP1 with drugs is a potential treatment for cancer, especially breast and ovarian cancer. In this study, we performed virtual screening on a database containing about 1.37 million molecules using the pharmacophore model, multiple precision molecular docking algorithms, molecular mechanics/generalized born surface area (MM/GBSA), strain energy, and ADMET screening methods. We found that Z28551960, Z423064076, Z1037335610, and Z1129923146 compounds showed excellent performance in terms of binding energy with USP1, ADMET property evaluation, and binding dynamics with USP1, had high potential as USP1 inhibitors, and were identified as hits in virtual screening. In addition, we demonstrated for the first time through molecular dynamics simulations that those molecules can enhance the structural flexibility of the USP1 protein and reduce its structural compactness, providing a basis for protein conformational changes. In summary, our discovery of potential USP1 inhibitors with novel scaffolds provides a theoretical basis for further development of USP1 inhibitors.

Identification of key mutations responsible for the enhancement of receptor-binding affinity and immune escape of SARS-CoV-2 Omicron variant

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns worldwide due to its enhanced transmissibility and immune escapability. The first dominant Omicron BA.1 subvariant harbors more than 30 mutations in the spike protein from the prototype virus, of which 15 mutations are located at the receptor binding domain (RBD). These mutations in the RBD region attracted significant attention, which potentially enhance the binding of the receptor human angiotensin-converting enzyme 2 (hACE2) and decrease the potency of neutralizing antibodies/nanobodies. This study applied the molecular dynamics simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method, to investigate the molecular mechanism behind the impact of the mutations acquired by Omicron on the binding affinity between RBD and hACE2. Our results indicate that five key mutations, i.e., N440K, T478K, E484A, Q493R, and G496S, contributed significantly to the enhancement of the binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that the key mutations E484A and Y505H reduce the binding affinities to RBD for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs.

Computer-aided drug design approaches applied toscreen natural product's structural analogs targeting arginase in Leishmania spp.

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics-generalized Born surface area (MM-GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.

The inhibitory potential of chemical constituents of Ficus carica targeting interleukin-6 (IL-6) mediated inflammation.

Inflammation is an innate reaction of the body of an individual when subjected to the noxious factors repeatedly. Pharmacological approaches focused at disrupting cytokine signaling networks have become significant therapeutic alternatives for the treatment of inflammatory illnesses, cancer and autoimmune disorders. High levels of inflammatory mediators, particularly interleukin IL-1, IL-6, IL-18, IL-12, and tumor necrosis factor alpha leads to a cytokine storm in the body. Among all the released cytokines in a patient suffering from inflammatory disorder, IL-6 mediator has a pivotal role in this inflammatory cascade which progresses to a cytokine storm. Therefore, the blockage of the IL-6 inflammatory mediator could be a promising treatment option for the patients with hyper inflammatory conditions. The phytochemicals could provide the new lead compounds against the IL-6 mediator. Ficus carica has been the ideal plant of research and investigation due to its commercial, economic and medical importance. The anti-inflammatory properties of F. carica were further investigated by in silico and in vivo approaches. The docking scores of Cyanidin-3,5-diglucoside, Kaempferol-7-O-rutinoside, Cyanidin-3-rhamnoglucoside, and Rutin are -9.231, -8.921, -8.840, and -8.335 Kcal/mole respectively. The free energy of binding and stability of the docked complexes of these top four phytochemicals with the IL-6 were further analyzed by Molecular Mechanics-Generalized Born Surface Area and Molecular Dynamic simulations, respectively. The in vivo anti-inflammatory carrageenan-induced rat paw edema model was used for the validation of in silico results. The maximum percentage paw edema inhibition with petroleum ether and ethyl acetate was 70.32% and 45.05%, respectively. The in vivo anti-inflammatory activity confirms the anti-inflammatory potential of F. carica. Therefore, it is predicted that Cyanidin-3,5-diglucoside, Kaempferol-7-O-rutinoside, Cyanidin-3-rhamnoglucoside, and Rutin have the potential to inhibit the IL-6 mediator which will aid in mitigating the cytokine storm in patients with acute inflammations.

Computational drug repurposing of Akt-1 allosteric inhibitors for non-small cell lung cancer

Non-small cell lung carcinomas (NSCLC) are the predominant form of lung malignancy and the reason for the highest number of cancer-related deaths. Widespread deregulation of Akt, a serine/threonine kinase, has been reported in NSCLC. Allosteric Akt inhibitors bind in the space separating the Pleckstrin homology (PH) and catalytic domains, typically with tryptophan residue (Trp-80). This could decrease the regulatory site phosphorylation by stabilizing the PH-in conformation. Hence, in this study, a computational investigation was undertaken to identify allosteric Akt-1 inhibitors from FDA-approved drugs. The molecules were docked at standard precision (SP) and extra-precision (XP), followed by Prime molecular mechanics—generalized Born surface area (MM-GBSA), and molecular dynamics (MD) simulations on selected hits. Post XP-docking, fourteen best hits were identified from a library of 2115 optimized FDA-approved compounds, demonstrating several beneficial interactions such as pi–pi stacking, pi-cation, direct, and water-bridged hydrogen bonds with the crucial residues (Trp-80 and Tyr-272) and several amino acid residues in the allosteric ligand-binding pocket of Akt-1. Subsequent MD simulations to verify the stability of chosen drugs to the Akt-1 allosteric site showed valganciclovir, dasatinib, indacaterol, and novobiocin to have high stability. Further, predictions for possible biological interactions were performed using computational tools such as ProTox-II, CLC-Pred, and PASSOnline. The shortlisted drugs open a new class of allosteric Akt-1 inhibitors for the therapy of NSCLC.

Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis.

Visceral leishmaniasis (VL) is caused by Leishmania donovani (Ld), and most cases occur in Brazil, East Africa, and India. The treatment for VL is limited and has many adverse effects. The development of safer and more efficacious drugs is urgently needed. Drug repurposing is one of the best processes to repurpose existing drugs. Ornithine decarboxylase (ODC) is an important target against L. donovani in the polyamine biosynthesis pathway. In this study, we have modeled the 3D structure of ODC and performed high-throughput virtual screening of 8630 ZINC database ligands against Leishmania donovani ornithine decarboxylase (Ld ODC), selecting 45 ligands based on their high binding score. It is further validated through molecular docking simulation and the selection of the top two lead molecules (ceftaroline fosamil and rimegepant) for Molecular Dynamics (MD) simulation, Density functional theory (DFT), and molecular mechanics generalized born surface area (MMGBSA) analysis. The results showed that the binding affinities of ceftaroline fosamil, and rimegepant are, respectively, -10.719 and 10.159 kcal/mol. The docking complexes of the two lead compounds, ceftaroline fosamil, and rimegepant, with the target ODC, were found stable during molecular dynamics simulations. Furthermore, the analysis of MMGBSA revealed that these compounds had a high binding free energy. The DFT analysis showed that the top lead molecules were more reactive than the standard drug (pentamidine). In-silico findings demonstrated that ceftaroline fosamil, and rimegepant might be recognized as potent antagonists against ODC for the treatment of VL.