The binding pose and affinity between a ligand enzyme are very important pieces of information for computer-aided drug design. In the initial stage discovery project, this is often obtained by using molecular docking methods. Autodock4 Autodock Vina two commonly used open-source free software tools to perform task, each has been cited more than 6000 times in last ten years. It great interest compare success rate programs large diverse set protein–ligand complexes. study, we selected 800...

Fast lateral proton migration along membranes is of vital importance for cellular energy homeostasis and various proton-coupled transport processes. It can only occur if attractive forces keep the at interface. How to reconcile this high affinity membrane surface with mobility unclear. Here, we tested whether a minimalistic model interface between an apolar hydrophobic phase (n-decane) aqueous mimics biological pathway migration. The observed diffusion span, on order tens micrometers, were...

The COVID-19 pandemic has killed millions of people worldwide since its outbreak in December 2019. is caused by the SARS-CoV-2 virus whose main protease (Mpro) a promising drug target it plays key role viral proliferation and replication. Currently, developing an effective therapy urgent task, which requires accurately estimating ligand-binding free energy to Mpro. However, should be noted that accuracy method probably depends on protein target. A highly accurate approach for some targets...

Proton diffusion along biological membranes is vitally important for cellular energetics. Here we extended previous time-resolved fluorescence measurements to study the time and temperature dependence of surface proton transport. We determined Gibbs activation energy barrier ΔG ‡r that opposes surface-to-bulk release from Arrhenius plots (i) protons' constant (ii) rate coefficient release. The large size disproves quasi-equilibrium exists in our experiments between protons near-membrane...

Abstract AutoDock Vina (Vina) achieved a very high docking‐success rate, , but give rather low correlation coefficient, for binding affinity with respect to experiments. This can be an obstacle ranking of ligand‐binding affinity, which is the main objective docking simulations. In this context, we evaluated dependence R coefficient upon its empirical parameters. affected more by changing gauss2 and rotation than other terms. The rate sensitive alterations gauss1, gauss2, repulsion, hydrogen...

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the COVID-19 pandemic, resulting in several million deaths being reported. Numerous investigations have carried out to discover a compound that can inhibit biological activity of SARS-CoV-2 main protease, which is an enzyme related viral replication. Among these, PF-07321332 (Nirmatrelvir) currently under clinical trials for therapy. Therefore, this work, atomistic and electronic simulations were performed...

The inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) presents a promising therapeutic strategy for treating Alzheimer's disease (AD) by reducing amyloid-beta (Aβ) production. Despite the potential BACE1 inhibitors, their clinical application has been hindered challenges related to toxicity and efficacy. In this paper employed computational approach which combines machine learning atomistic simulations accelerate discovery effective inhibitors. Our ML models trained on...

Determination of the ligand‐binding affinity is an extremely interesting problem. Normally, free energy perturbation (FEP) method provides appropriate result. However, it great interest to improve accuracy and precision this method. In context, temperature replica exchange molecular dynamics implementation FEP computational approach, which we call (REP) was proposed. particular, during REP simulations, system can easily escape from being trapped in local minima by exchanging configurations...

A combination of Autodock Vina and FPL calculations suggested that<italic>periandrin V</italic>,<italic>penimocycline</italic>,<italic>cis-p-Coumaroylcorosolic acid</italic>,<italic>glycyrrhizin</italic>, and<italic>uralsaponin B</italic>are able to bind well SARS-CoV-2 Mpro.

Acetylcholinesterase (AChE) is one of the most important drug targets for Alzheimer's disease (AD) treatment. In this work, a machine learning model was trained to rapidly and accurately screen large chemical databases potential inhibitors AChE. The obtained results were then validated via in vitro enzyme assay. Moreover, atomistic simulations including molecular docking dynamics used understand insights into binding process ligands particular, two compounds benzyl trifluoromethyl ketone...

FEP calculation performance depends on the considered targets.

MedChemExpress compounds prevent neuraminidase N1 via physics- and knowledge-based methods.

We demonstrate the feasibility of estimating protein-ligand binding free energies using multiple rigid receptor configurations. On basis T4 lysozyme snapshots extracted from six alchemical energy calculations with a flexible receptor, were estimated for total 141 ligands. For 24 ligands, reproduced flexible-receptor estimates correlation coefficient 0.90 and root-mean-square error 1.59 kcal/mol. The accuracy based on Poisson-Boltzmann/surface area implicit solvent was comparable to that...

The ordering of the classical Heisenberg model on pyrochlore lattice with antiferromagnetic nearest-neighbor interaction J1 and ferromagnetic next-nearest-neighbour J2 is investigated by means a mean-field analysis Monte Carlo simulation. For moderate J2/J1-value, exhibits first-order transition into an incommensurate multiple-q ordered state where multiple Bragg peaks coexist in spin structure factor. We show that there are two types metastable states, cubic symmetric sextuple-q non-cubic...

Isothermal titration calorimetry (ITC) is the only technique able to determine both enthalpy and entropy of noncovalent association in a single experiment. The standard data analysis method based on nonlinear regression, however, provides unrealistically small uncertainty estimates due its neglect dominant sources error. Here, we present Bayesian framework for sampling from posterior distribution all thermodynamic parameters other quantities interest one or more ITC experiments, allowing...

The umbrella sampling (US) simulation is demonstrated to be an efficient approach for determining the unbinding pathway and binding affinity SARS-CoV-2 Mpro of small molecule inhibitors. accuracy US in same range as linear interaction energy (LIE) fast pulling ligand (FPL) methods. In detail, correlation coefficient between experiments does not differ from FPL slightly smaller than LIE. root mean square error simulations that Moreover, better poorer LIE classifying inhibitors owing reciever...

Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of BACE1. particular, potential inhibitory compounds was rapidly accurately estimated via knowledge-methods. The in vitro tests then performed validate artificial intelligent approach. Among these, compound 12 exhibited most potent inhibition an IC50 15.68...

Background: The application of molecular docking and Machine Learning (ML) calculations in evaluating peptide-based inhibitors allows for the systematic investigation sequenceactivity relationships, guiding design potent peptides with optimal binding characteristics. Objective: This study aimed to screen short using computational simulation identify promising against SARS-CoV-2 Mpro. Methods: Short were screened candidates. ML model was applied confirm outcome. PreADME server then used...

Computational identification of tripeptides as promising dual AChE/BACE-1 inhibitors for Alzheimer's therapy.

The cellular uptake of cisplatin and other platinum-based drugs is mediated by the high-affinity copper transporter Ctr1. eight-residue long peptide called Mets7 (MTGMKGMS) mimics one extracellular methionine (Met)-rich motifs It an excellent model for investigating interaction platinum with Ctr1 under in vitro vivo conditions. Some us have shown that (i) Cisplatin loses all its ligands upon reaction metal ion binds to three Met residues completes coordination shell a fourth ligand can be...

The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by emergence resistance. This related to binding proteins such as copper influx transporter Ctr1, chaperone Atox1, and pumps ATP7A ATP7B. While modes first two are known, structural determinants platinated ATP7A/ATP7B lacking. Here we investigate interaction with soluble domain ATP7A. First, establish ESI-MS (1)H, (13)C, (15)N NMR that, in solution, adduct a monomer which sulfur atoms residues Cys19 Cys22...

Alzheimer's disease displays aggregates of the amyloid-beta (Aβ) peptide in brain, and there is increasing evidence that cholesterol may contribute to pathogenesis disease. Though many experimental theoretical studies have focused on interactions Aβ oligomers with membrane models containing cholesterol, an understanding effect free small Aβ42 not fully established. To address this question, we report replica exchange a solute tempering simulation trimer compare it previous molecular dynamics...