In Silico Pharmacology最新文献

Human toxoplasmosis is a global public health concern and a commercial vaccine is still lacking. The present in silico study was done to design a novel vaccine candidate using tachyzoite-specific SAG1-realted sequence (SRS) proteins. Overlapping B-cell and strictly-chosen human MHC-I binding epitopes were predicted and connected together using appropriate spacers. Moreover, a TLR4 agonist, human high mobility group box protein 1 (HMGB1), and His-tag were added to the N- and C-terminus of the vaccine sequence. The final vaccine had 442 residues and a molecular weight of 47.71 kDa. Physico-chemical evaluation showed a soluble, highly antigenic and non-allergen protein, with coils and helices as secondary structures. The vaccine 3D model was predicted by ITASSER server, subsequently refined and was shown to possess significant interactions with human TLR4. As well, potent stimulation of cellular and humoral immunity was demonstrated upon chimeric vaccine injection. Finally, the outputs showed that this vaccine model possesses top antigenicity, which could provoke significant cell-mediated immune profile including IFN-γ, and can be utilized towards prophylactic purposes.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-023-00140-w.

Benign Prostatic Hyperplasia (BPH) is a major cause of lower urinary tract infections and erectile dysfunction thus a major contributor to lowering the quality of life among older men. In this study, we investigated the molecular mechanism of Colocasia esculenta (CE) as a novel agent for BPH chemotherapy. In vivo, we assigned 45 male Wistar albino rats about 6 weeks old into 9 experimental groups (n = 5). BPH was induced in groups 2-9 with 3 mg/kg of Testosterone Propionate (TP) subcutaneously. Group 2 (BPH) was not treated. Group 3 was treated with 5 mg/kg Finasteride (standard drug). Group 4-9 were treated each with 200 mg/kg body weight (b.w) of CE crude tuber extracts/fractions (ethanol, hexane, dichloromethane, ethyl acetate, butanol, aqueous). At the end of treatment, we sampled the rats' serum to check the level of PSA. In silico, we conducted a molecular docking of the crude extract of CE phenolics (CyP) previously reported, targeting 5α-Reductase and α1-Adrenoceptor linked to the BPH progressions. We adopted the standard inhibitors/antagonists (5α-reductase: finasteride; α1-adrenoceptor: tamsulosin) of the target proteins as controls. Furthermore, the pharmacological properties of the lead molecules were studied in terms of ADMET using swissadme and pKCSM resources, respectively. Results showed that administration of TP in male Wistar albino rats significantly (p < 0.05) elevated serum PSA levels whereas CE crude extracts/fractions significantly (p < 0.05) lowered the serum PSA level. Also, fourteen of the CyPs bind to at least one or two of the target proteins with their binding affinity of between - 9.3 to - 5.6 kcal/mol and - 6.9 to - 4.2 kcal/mol, respectively. The CyPs possess better pharmacological properties compared to the standard drugs. Therefore, they have the potentials to be enlisted for clinical trials towards the management of BPH.

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HCV is a hepatotropic RNA virus recognized for its frequent virulence and fatality worldwide. Despite many vaccine development programs underway, researchers are on a quest for natural bioactive compounds due to their multivalent efficiencies against viral infections, considering which the current research aimed to figure out the target-specificity and therapeutic potentiality of α, β, and δ subunits of amyrin, as novel bioactive components against the HCV influx mechanism. Initially, the novelty of amyrin subunits was conducted from 203 pharmacophores, comparing their in-silico pharmacokinetic and pharmacodynamic profiles. Besides, the best active site of CD81 was determined following the quantum tunneling algorithm. The molecular dynamic simulation was conducted (100 ns) following the molecular docking steps to reveal the parameters- RMSD (Å); Cα; RMSF (Å); MolSA (Ų); Rg (nm); PSA (Å); SASA (Ų), and the MM-GBSA dG binding scores. Besides, molecular strings of CD81, along with the co-expressed genes, were classified, as responsible for encoding CD81-mediated protein clusters during HCV infection, resulting in the potentiality of amyrins as targeted prophylactics in HCV infection. Finally, in vivo profiling of the oxidative stress marker, liver-specific enzymes, and antioxidant markers was conducted in the DMN-induced mice model, where β-amyrin scored the most significant values in all aspects.

A 336-base pair (bp) sized mRNA sequence encoding 111 amino acid size crustin isoform (MC-crustin) was obtained from the gill sample of the green mud crab, Scylla serrata. MC-crustin possessed an N-terminal signal peptide region comprising of 21 amino acid residues, followed by a 90 amino acid mature peptide region having a molecular weight of 10.164 kDa, charge + 4.25 and theoretical pI of 8.27. Sequence alignment and phylogenetic tree analyses revealed the peptide to be a Type I crustin, with four conserved cysteine residues forming the cysteine rich region, followed by WAP domain. MC-crustin was cationic with cysteine/proline rich structure and was predicted with antimicrobial, anti-inflammatory, anti-angiogenic and anti-hypertensive property making it a potential molecule for possible therapeutic applications.

Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson's disease. Recently, hMAO-B and hA_2AR Dual-targets inhibitory potential of a novel series of Phenylxanthine derivatives has been established in experimental findings. Hence, the current study examines the interactions between 38 compounds of this series with hMAO-B and hA_2AR targets using different molecular modeling techniques to investigate the binding mode and stability of the formed complexes. A molecular docking study revealed that the compounds L24 ((E)-3-(3-Chlorophenyl)-N-(4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and L32 ((E)-3-(3-Chlorophenyl)-N-(3-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acrylamide) had a high affinity (S-score: -10.160 and -7.344 kcal/mol) with the pocket of hMAO-B and hA_2AR targets respectively, and the stability of the studied complexes was confirmed during MD simulations. Also, the MEP maps of compounds 24 and 32 were used to identify the nucleophilic and electrophilic attack regions. Moreover, the bioisosteric replacement approach was successfully applied to design two new analogs of each compound with similar biological activities and low energy scores. Furthermore, ADME-T and Drug-likeness results revealed the promising pharmacokinetic properties and oral bioavailability of these compounds. Thus, compounds L24, L32, and their analogs can undergo further analysis and optimization in order to design new lead compounds with higher efficacy toward Parkinson's disease.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-023-00139-3.

Introduction: Toll-like receptor 4 (TLR4) has attracted interest due to its role in chemotherapy-induced gastrointestinal inflammation. This structural study aimed to provide in silico rational of the recognition and potential binding of TLR4 ligands IAXO-102, TAK-242, and SN-38 (the toxic metabolite of the chemotherapeutic irinotecan hydrochloride), which could contribute to rationale development of therapeutic anti-inflammation drugs targeting TLR4 in the gastrointestinal tract.

Methods: In silico docking was performed between the human TLR4-MD-2 complex and ligands (IAXO-102, TAK-242, SN-38) using Autodock Vina, setting the docking grids to cover either the upper or the lower bound of TLR4. The conformation having the lowest binding energy value (kcal/mol) was processed for post-hoc analysis of the best-fit model. Hydrogen bonding was calculated by using ChimeraX.

Results: Binding energies of IAXO-102, TAK-242 and SN-38 at the upper bound of TLR4-MD-2 ranged between - 3.8 and - 3.1, - 6.9 and - 6.3, and - 9.0 and - 7.0, respectively. Binding energies of IAXO-102, TAK-242 and SN-38 at the lower bound ranged between - 3.9 and - 3.5, - 6.5 and - 5.8, and - 8.2 and - 6.8, respectively. Hydrogen bonding at the upper bound of TLR4/MD-2 with IAXO-102, TAK-242 and SN-38 was to aspartic acid 70, cysteine 133 and serine 120, respectively. Hydrogen bonding at the lower bound of TLR4-MD-2 with IAXO-102, TAK-242 and SN-38 was to serine 528, glycine 480 and glutamine 510, respectively.

Conclusion: The in silico rational presented here supports further investigation of the binding activity of IAXO-102 and TAK-242 for their potential application in the prevention of gastrointestinal inflammation caused by SN-38.

Lymphatic filariasis and onchocerciasis are common filarial diseases caused by filarial worms, which co-habit symbiotically with the Wolbachia organism. One good treatment method seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening and 3-D QSAR modeling were conducted on a series of Fifty-two (52) pyrazolopyrimidine derivatives against four Wolbachia receptors, including a pharmacokinetics study and Molecular Dynamic (MD) investigation, to find a more potent anti-filarial drug. The DFT approach (B3LYP with 6-31G** option) was used for the structural optimization. Five ligand-protein interaction pairs with the highest binding affinities were identified in the order; 23_7ESX (-10.2 kcal/mol) > 14_6EEZ (- 9.0) > 29_3F4R (- 8.0) > 26_6W9O (- 7.7) ≈ doxycycline_7ESX (- 7.7), with good pharmacological interaction profiles. The built 3-D QSAR model satisfied the requirement of a good model with R² = 0.9425, Q² _LOO = 0.5019, SDEC = 0.1446, and F test = 98.282. The selected molecules (14, 23, 26, and 29) perfectly obeyed Lipinski's RO5 for oral bio-availability, and showed excellent ADMET properties, except 14 with positive AMES toxicity. The result of the MD simulation showed the great stability associated with the binding of 23 onto 7ESX's binding pocket with an estimated binding free energy (MM/GBSA) of - 60.6552 kcal/mol. Therefore, 23 could be recommended as a potential anti-filarial drug molecule, and/or template for the design of more prominent inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-022-00136-y.

Angiotensin converting enzyme (ACE) is a key enzyme and mediator in the aetiology of high blood pressure (HBP) and hypertension. As one of the leading cause of untimely death worldwide, there is a lot of research and studies on the management and treatment of hypertension. The usage of medicinal plants in the management of hypertension as alternative to synthetic allopathic drugs is a common practice in folkloric and traditional medicine. Therefore, this study was aimed to investigate the ACE inhibitory activity of some medicinal plants which are commonly used in the treatment of HBP in southwestern part of Nigeria using extensive in-silico approach. Compounds identified in the plants through GC-MS technique, together with Lisinopril were docked against ACE protein. It was observed that only 40 of the compounds had binding affinity ≥ - 6.8 kcal/mol which was demonstrated by the standard drug (lisinopril). Interaction between the compounds and ACE was via conventional hydrogen, carbon hydrogen, alkyl, pi-alkyl, pi-carbon, and Van Der Wall bonds among others. Most of these compounds exhibited drug like properties, without violating majority of the physicochemical descriptors and Lipinski rule of 5. The ADMET evaluation revealed that only 2 compounds (cyclopentadecanone and oxacycloheptadecan-2-one) which were identified in Bacopa florinbunda plant were predicted non-toxic and thus were subjected to molecular dynamics and simulation with ACE. From the molecular dynamics and mechanics analysis, both cyclopentadecanone and oxacycloheptadecan-2-one showed high stability and inhibitory potentials when bound to ACE. Oxacycloheptadecan-2-one was more stable than lisinopril and cyclopentadecanone in the ligand-ACE complex; we therefore suggested its experimental and clinical validation as drug candidates for the treatment of hypertension.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-022-00135-z.

The healing of wound is a tightly-regulated cascade of events, involving interplay of enormous factors. Now a days, pain alleviation and faster wound healing have attracted considerable attention. Several natural compounds have played crucial role in this intriguing process. The present study deals with five selected molecules from the plant Mallotus philippensis (Lam.) Mull. Arg. targeting the eight essential proteins involved in the wound healing and inflammatory process. Considering that various phytoconstituents of medicinal plant can simultaneously interacts with multiple targets, in current work multiligand and multitarget approach was employed instead of traditional one ligand-multitarget approach. Docking studies were performed using AutoDock Vina and molecular dynamics was performed using GROMACS 2019. The current study revealed the potential interactions of five selected constituents with multiple chronic wound healing targets. The wound healing effect of Mallotus philippensis (Lam.) Mull. Arg. fruits may be due to combined effect of all these compounds. Effective interactions with the amino acid residues present in the active site of some of the essential proteins involved in the wound healing process also suggests possible mechanism in the wound healing process. The current work thus provides a meaningful insight that Mallotus philippensis (Lam.) Mull. Arg. fruits could be used as potential candidate for faster healing of wound. Also, in silico studies depicting interaction with the targets and receptors provide a meaningful insight that this plant would be used as potential candidate for new drug development.

Alzheimer's disease (AD) is a distinctive medical condition characterized by loss of memory, orientation, and cognitive impairments, which is an exceptionally universal form of neurodegenerative disease. The statistical data suggested that it is the 3rd major cause of death in older persons. Butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors play a vital role in the treatment of AD. Coumarins, natural derivatives, are reported as cholinesterase inhibitors and emerges as a promising scaffold for design of ligands targeting enzymes and pathological alterations related to AD. In this regard, the 3D QSAR pharmacophore models were developed for coumarin scaffold containing BChE and AChE inhibitors. Several 3D QSAR pharmacophore models were developed with FAST, BEST, and CEASER methods, and finally, statistically robust models (based on correlation coefficient, cost value, and RMSE value) were selected for further analysis for both targets. The important features ((HBA 1, HBA 2, HY, RA (BChE) HBA 1, HBA 2, HY, PI, (AChE)) were identified for good inhibitory activity of coumarin derivatives. Finally, the selected models were applied to various database compounds to find potential BChE and AChE inhibitors, and we found 13 for BChE and 1 potent compound for AChE with an estimated activity of IC₅₀ < 10 µM. Further, the Lipinski filters, and ADMET analysis supports the selected compounds to become a drug candidate. These selected BChE and AChE inhibitors can be used in the treatment of AD.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-022-00133-1.