Binding Affinity Calculations Research Articles

Unraveling the folding-assisted unbinding mechanism of TCF with its binding partner β-catenin.

This study utilizes molecular dynamics simulations aided with multiple walker parallel bias metadynamics to investigate the TCF unbinding mechanism from the β-catenin interface. The results, consistent with experimental binding affinity calculations, unveil a folding-assisted unbinding mechanism.

Interface‐Guided Computational Protein Design Reveals Bebtelovimab‐Resistance Mutations in SARS‐CoV‐2 RBD: Correlation with Global Viral Genomes and Bebtelovimab‐Escape Mutations

AbstractThe emergence of novel mutations in the SARS‐CoV‐2 spike protein challenges monoclonal antibody (mAb) effectiveness. Comprehending resistance mutations and pinpointing vulnerable spike protein residues is vital for enhanced antibody design. To address this issue, we employed an interface‐guided computational protein design (CPD) approach to decode bebtelovimab‐resistance mutations and uncover susceptible residues within the receptor‐binding domain (RBD). Utilizing structural‐modeling and high‐throughput techniques, we mapped the bebtelovimab‐RBD interface, identifying critical resistance mutations through analysis of binding energetics and residue interactions. Our design protocol integrated stability predictions, side‐chain conformational sampling, and binding affinity calculations to prioritize substitutions that restore antibody recognition and neutralization. Previously unexplored susceptible RBD residues were also discovered, offering new therapeutic avenues. Comparative analysis with COVID‐19 patient data validated the predicted resistance mutations (69 %–100 % correlation, based on different MinProp cut‐offs). Precision and recall values, calculated by comparing our predictions with experimentally reported bebtelovimab‐escape mutants, demonstrated the performance and accuracy of our predictions. Investigation of intermolecular interactions highlighted the importance of van der Waals forces, hydrogen bond energy, and electrostatic contributions in bebtelovimab‐RBD binding affinity. This computational design empowers the decoding of resistance mutations and the development of next‐generation antibodies against viral variants, strengthening our response to SARS‐CoV‐2 and related coronaviruses.

Synthesis, antimicrobial activity and molecular docking study of benzyl functionalized benzimidazole silver(I) complexes.

In this study, a series of N-functionalized benzimidazole silver(I) complexes were prepared and characterized by FT-IR, 1H, 13C{1H} NMR spectroscopy, and elemental analysis. Synthesized N-benzylbenzimidazole silver(I) complexes were evaluated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. The results indicated that N-alkylbenzimidazole silver(I) complexes exhibited good antimicrobial activity compared to N-alkylbenzimidazole derivatives. Especially, complex 2e presented perfect antimicrobial activity than the other complexes. The characterized molecules were optimized by DFT-based calculation methods and the optimized molecules were analyzed in detail by molecular docking methods against bacterial DNA-gyrase and CYP51. The amino acid residues detected for both target molecules are consistent with expectations, and the calculated binding affinities and inhibition constants are promising for further studies. A series of N-alkylbenzimidazole silver(I) complexes were synthesized and fully characterized by means of 1H NMR, 13C NMR, and FT-IR spectroscopies. Synthesized N-alkylbenzimidazole silver(I) complexes were investigated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. All complexes showed better activity according to Ampicilin against Pseudomonas aeruginosa. The molecules which were firstly optimized by DFT-based calculation methods were also analyzed by molecular docking methods against DNA gyrase of E. Coli and CYP51. 338 × 190mm (96 × 96 DPI).

Leveraging QM/MM and Molecular Dynamics Simulations to Decipher the Reaction Mechanism of the Cas9 HNH Domain to Investigate Off-Target Effects.

The clustered regularly interspaced short palindromic repeats (CRISPR) technology is an RNA-guided targeted genome-editing tool using Cas family proteins. Two magnesium-dependent nuclease domains of the Cas9 enzyme, termed HNH and RuvC, are responsible for cleaving the target DNA (t-DNA) and nontarget DNA strands, respectively. The HNH domain is believed to determine the DNA cleavage activity of both endonuclease domains and is sensitive to complementary RNA-DNA base pairing. However, the underlying molecular mechanisms of CRISPR-Cas9, by which it rebukes or accepts mismatches, are poorly understood. Thus, investigation of the structure and dynamics of the catalytic state of Cas9 with either matched or mismatched t-DNA can provide insights into improving its specificity by reducing off-target cleavages. Here, we focus on a recently discovered catalytic-active form of the Streptococcus pyogenes Cas9 (SpCas9) and employ classical molecular dynamics and coupled quantum mechanics/molecular mechanics simulations to study two possible mechanisms of t-DNA cleavage reaction catalyzed by the HNH domain. Moreover, by designing a mismatched t-DNA structure called MM5 (C to G at the fifth position from the protospacer adjacent motif region), the impact of single-guide RNA (sgRNA) and t-DNA complementarity on the catalysis process was investigated. Based on these simulations, our calculated binding affinities, minimum energy paths, and analysis of catalytically important residues provide atomic-level details of the differences between matched and mismatched cleavage reactions. In addition, several residues exhibit significant differences in their catalytic roles for the two studied systems, including K253, K263, R820, K896, and K913.

Efficient Ru-Catalyzed Electrochemical Homo- and Heterocoupling Reaction of Terminal Alkynes: Synthesis, In Vitro Anticancer Activity, and Docking Study.

With the objective to identify novel anticancer leads, herein ruthenium-catalyzed electrochemical homo- and heterocoupling reactions of terminal alkynes have been developed for the synthesis of the desired products. Among the synthesized 1,3-diynes, some of them were rigorously examined for possible in vitro anticancer activity against HeLa (human cervical cancer) and L6 normal (rat skeletal muscle) cell lines. Additionally, the docking study was also performed toward 16 ovarian cancer targets with binding affinity calculations with respect to the standard. To the best of our knowledge, this is the first scientific report on the ruthenium-catalyzed electrochemical homocoupling reaction between terminal alkynes with its in vitro anticancer and in silico docking studies.

Evolution of Organic Solvent-Resistant DNA Polymerases.

The introduction of thermostable polymerases revolutionized the polymerase chain reaction (PCR) and biotechnology. However, many GC-rich genes cannot be PCR-amplified with high efficiency in water, irrespective of temperature. Although polar organic cosolvents can enhance nucleic acid polymerization and amplification by destabilizing duplex DNA and secondary structures, nature has not selected for the evolution of solvent-tolerant polymerase enzymes. Here, we used ultrahigh-throughput droplet-based selection and deep sequencing along with computational free-energy and binding affinity calculations to evolve Taq polymerase to generate enzymes that are both stable and highly active in the presence of organic cosolvents, resulting in up to 10% solvent resistance and over 100-fold increase in stability at 97.5 °C in the presence of 1,4-butanediol, as well as tolerance to up to 10 times higher concentrations of the potent cosolvents sulfolane and 2-pyrrolidone. Using these polymerases, we successfully amplified a broad spectrum of GC-rich templates containing regions with over 90% GC content, including templates recalcitrant to amplification with existing polymerases, even in the presence of cosolvents. We also demonstrated dramatically reduced GC bias in the amplification of genes with widely varying GC content in quantitative polymerase chain reaction (qPCR). By expanding the scope of solvent systems compatible with nucleic acid polymerization, these organic solvent-resistant polymerases enable a dramatic reduction of sequence bias not achievable through thermal resistance alone, with significant implications for a wide range of applications including sequencing and synthetic biology in mixed aqueous-organic media.

Some morpholine tethered novel aurones: Design, synthesis, biological, kinetic and molecular docking studies

Enzymes are the biological macromolecules that have emerged as an important drug target as their upregulation/imbalance leads to various pathological conditions, such as inflammation, parasitic infection, Alzheimer’s, cancer, and many others. Here, we designed and synthesized some morpholine tethered novel aurones and evaluated them as potential inhibitors for CTSB, α-amylase, lipase and activator for trypsin. All the newly synthesized compounds were fully characterized by various spectroscopic techniques (1H NMR, 13C NMR, HRMS) and the Z-configuration to them was assigned based on single crystal XRD data and 1H NMR chemical shift values. Further, the hybrids were evaluated for their intracellular (cathepsin B) and extracellular (trypsin, lipase, amylase) enzyme inhibition potencies. The in-vitro inhibition screening against cathepsin B revealed that most of the synthesized compounds are good competitive inhibitors (% inhibition = 22.91–75.04), with 6q (% inhibition = 75.04) and 6r (% inhibition = 71.13) as the eminent inhibitors of the series. At the same time, they exhibited weak to moderate inhibition towards amylase (% inhibition = 7.22–22.48) and lipase (% inhibition = 16.29–54.83). A significant trypsin activation (% activation = 107.42–196.47) was observed even at the micromolar concentration of the compounds. Furthermore, the drug-modeling studies showed a good correlation between the in-vitro experimental results and the calculated binding affinity of the screened compounds with all the tested enzymes. These findings are expected to provide a new lead in drug development for different pathological disorders wherever these enzymes are involved.

Facile Synthesis of Bis‐Coumarins Using [BCMIM][Cl] Zwitter Ionic Liquid and Their Binding with Bovine Serum Albumin

AbstractHerein, we report a novel synthetic pathway for synthesizing bis‐coumarins using 5 mol% [BCMIM][Cl] ionic liquid via the facile, one‐pot, metal‐free synthesis in aqueous ethanol at room temperature. A series of 24 derivatives were furnished in up to 94% yields in 15 min to 1.5 h and were characterized using different spectroscopic techniques. The photophysical properties of bis‐coumarin derivatives were explored through UV‐Visible and fluorescence spectroscopy. The absorption and emission spectra demonstrate a peak wavelength (λmax), within the range of 297–311 nm and 486–505 nm, respectively. An analogous pattern to the experimental results is seen in density functional calculations. The binding affinities of all the synthesised derivatives with Bovine Serum Albumin (BSA) were determined using AutoDock Vina which exhibited a range from −8.4 to −11.5 kcal mol−1. The computed binding constant (KBSA) by tryptophan (Trp) emission quenching values illustrate strong binding interactions of the selected ligands in the order of 104. The calculated binding affinities were validated by performing molecular dynamics simulations of the best docking pose using GROMACS software over a period of 1 ns for studying the stability of protein‐ligand complexes.

Phenolic compounds as potential adenosine deaminase inhibitors: molecular docking and dynamics simulation coupled with MM-GBSA calculations.

Adenosine deaminase (ADA) is a Zn2+-containing enzyme that catalyzes the irreversible deamination of adenosine to inosine or deoxyadenosine to deoxyinosine. In addition to this enzymatic function, ADA mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. ADA is implicated in cardiovascular pathologies such as atherosclerosis and certain types of cancers, including lymphoma and leukemia. To date, only two drugs (pentostatin and cladribine) have been approved for the treatment of hairy cell leukemia. In search of natural ADA inhibitors, we demonstrated the binding of selected phenolic compounds to the active site of ADA using molecular docking and molecular dynamics simulation. Our results show that phenolic compounds (chlorogenic acid, quercetin, and hyperoside) stabilized the ADA complex by forming persistent interactions with the catalytically essential Zn2+ ion. Furthermore, MM-GBSA ligand binding affinity calculations revealed that hyperoside had a comparable binding energy score (ΔG = -46.56 ± 8.26kcal/mol) to that of the cocrystal ligand in the ADA crystal structure (PDB ID: 1O5R) (ΔG = -51.97 ± 4.70kcal/mol). Similarly, chlorogenic acid exhibited a binding energy score (ΔG = -18.76 ± 4.60kcal/mol) comparable to those of the two approved ADA inhibitor drugs pentostatin (ΔG = -14.54 ± 2.25kcal/mol) and cladribine (ΔG = - 25.52 ± 4.10kcal/mol) while quercetin was found to have modest binding affinity (ΔG = - 8.85 ± 7.32kcal/mol). This study provides insights into the possible inhibitory potential of these phenolic compounds against ADA.

Virtual prediction of Brown Rice Gamma Oryzanol as anti-inflammation via COX-1 and COX-2 inhibitions

Brown rice gamma oryzanol (GO) is an important bioactive compound with numerous potential health functions, such as anti-inflammatory and anti-diabetic. Cyclooxygenase (COX) is the enzyme that mediates the biological transformation of arachidonic acid (ARA) into prostaglandins (PGs) in the mechanism of inflammation. This study purposed to identify the potency of gamma oryzanol of brown rice as an anti-inflammatory compound via COX-1 and COX-2 inhibition. The three-dimensional structure of COX-1 and COX-2 was determined by binding affinity calculations from virtual molecular docking with gamma oryzanol ligand through in silico study. Arachidonic acid as native ligand of COX-1/COX-2 was performed as a control in this study. Gamma oryzanol (CIS 5282164) and arachidonic acid (CIS 444899) were downloaded in 3D-SDF format from the PubChem database. The three-dimensional model of COX-1 and COX-2 was acquired from the protein data bank (www.rscb.org) in PDB format. The molecular docking was performed by Vina Wizard integrated on PyRx version 0.8. The interaction between GO and COX-1/COX-2 was visualized using the Discovery Studio version 2022 software. Molecular dynamics (MD) simulation also used to analyze the stability of the protein-ligand complex. The results showed that brown rice gamma oryzanol binds to COX-1 and COX-2 at many active sites with strongest binding affinity compared to arachidonic acid, with energy binding -7.8 kcal/mol and -6.2 kcal/mol, respectively. This in silico study concluded that brown rice gamma oryzanol has potential function as an anti-inflammatory activity through COX-1 and COX-2 catalysis reduction.

Molecular properties and In silico bioactivity evaluation of (4-fluorophenyl)[5)-3-phen-(4-nitrophenyl yl-4,5-dihydro-1H-pyrazol-1-yl]methanone derivatives: DFT and molecular docking approaches

ObjectivesMolecular structures, spectroscopic properties, charge distributions, frontier orbital energies, nonlinear optical (NLO) properties and molecular docking simulations were analyzed to examine the bio-usefulness of a series of (4-fluorophenyl)[5-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]methanone derivatives. MethodsThe compounds were studied through computational methods. Equilibrium optimization of the compounds was performed at the B3LYP/6-31G(d,p) level of theory, and geometric parameters, frequency vibration, UV–vis spectroscopy and reactivity properties were predicted on the basis of density functional theory (DFT) calculations. ResultsThe energy gap (ΔEg), electron donating/accepting power (ω−/ω+) and electron density response toward electrophiles/nucleophiles calculated for M1 and M2 revealed the importance of substituent positioning on compound chemical behavior. In addition, ω−/ω+ and ΔEn/ΔEe indicated that M6 is more electrophilic because of the presence of two NO2 groups, which enhanced its NLO properties. The hyperpolarizability (β0) of the compounds ranged from 5.21 × 10−30 to 7.26 × 10−30 esu and was greater than that of urea; thus, M1–M6 were considered possible candidates for NLO applications. Docking simulation was also performed on the studied compounds and targets (PDB ID: 5ADH and 1RO6), and the calculated binding affinity and non-bonding interactions are reported. ConclusionThe calculated ω− and ω+ indicated the electrophilic nature of the compounds; M6, a compound with two NO2 groups, showed enhanced effects. Molecular electrostatic potential (MEP) analysis indicated that amide and nitro groups on the compounds were centers of electrophilic attacks. The magnitude of the molecular hyperpolarizability suggested that the entire compound had good NLO properties and therefore could be explored as a candidate NLO material. The docking results indicated that these compounds have excellent antioxidant and anti-inflammatory properties.

Improving Speed and Affordability without Compromising Accuracy: Standard Binding Free-Energy Calculations Using an Enhanced Sampling Algorithm, Multiple-Time Stepping, and Hydrogen Mass Repartitioning.

Accurate evaluation of protein-ligand binding free energies in silico is of paramount importance for understanding the mechanisms of biological regulation and providing a theoretical basis for drug design and discovery. Based on a series of atomistic molecular dynamics simulations in an explicit solvent, using well-tempered metadynamics extended adaptive biasing force (WTM-eABF) as an enhanced sampling algorithm, the so-called "geometrical route" offers a rigorous theoretical framework for binding affinity calculations that match experimental values. However, although robust, this strategy remains expensive, requiring substantial computational time to achieve convergence of the simulations. Improving the efficiency of the geometrical route, while preserving its reliability through improved ergodic sampling, is, therefore, highly desirable. In this contribution, having identified the computational bottleneck of the geometrical route, to accelerate the calculations we combine (i) a longer time step for the integration of the equations of motion with hydrogen-mass repartitioning (HMR), and (ii) multiple time-stepping (MTS) for collective-variable and biasing-force evaluation. Altogether, we performed 50 independent WTM-eABF simulations in triplicate for the "physical" separation of the Abl kinase-SH3 domain:p41 complex, following different HMR and MTS schemes, while tuning, in distinct protocols, the parameters of the enhanced-sampling algorithm. To demonstrate the consistency and reliability of the results obtained with the best-performing setups, we carried out quintuple simulations. Furthermore, we demonstrated the transferability of our method to other complexes by triplicating a 200 ns separation simulation of nine chosen protocols for the MDM2-p53:NVP-CGM097 complex. [Holzer et al. J. Med. Chem. 2015, 58, 6348-6358.] Our results, based on an aggregate simulation time of 14.4 μs, allowed an optimal set of parameters to be identified, able to accelerate convergence by a factor of three without any noticeable loss of accuracy.

On Ternary Complex Stability in Protein Degradation: In Silico Molecular Glue Binding Affinity Calculations.

Molecular glues are small molecules that simultaneously bind to two proteins, creating a chemically induced protein-protein interface. CELMoDs (cereblon E3 ligase modulators) are a class of molecular glues that promote recruitment of neosubstrate proteins to the E3 ubiquitin ligase cereblon (CRBN) for poly-Lys48-ubiquitination and proteasomal degradation. Ternary complex structures of clinical CELMoDs CC-885 and CC-90009 bound to CRBN and neosubstrate G1 to S phase transition protein 1 (GSPT1) have been experimentally determined. Although cellular degradation is a downstream event, dependent not only on the affinity of the glue CELMoD in the ternary complex, we test the applicability of established structure-based drug design principles to predict binding affinity of CELMoDs to the protein-protein neointerface and correlation to measured cellular degradation for the neosubstrates GSPT1 and zinc finger Aiolos (IKZF3). For a congeneric series of CELMoDs, which have a similar sequence of binding events and resultant binding modes, we conclude that well-established structure-based methods that measure in silico ternary complex stabilities can predict relative degradation potency by CELMoDs.

Identification of Natural Compounds of the Apple as Inhibitors against Cholinesterase for the Treatment of Alzheimer’s Disease: An In Silico Molecular Docking Simulation and ADMET Study

Alzheimer's disease (AD), the most common type of dementia in older people, causes neurological problems associated with memory and thinking. The key enzymes involved in Alzheimer's disease pathways are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Because of this, there is a lot of interest in finding new AChE inhibitors. Among compounds that are not alkaloids, flavonoids have stood out as good candidates. The apple fruit, Malus domestica (Rosaceae), is second only to cranberries regarding total phenolic compound concentration. Computational tools and biological databases were used to investigate enzymes and natural compounds. Molecular docking techniques were used to analyze the interactions of natural compounds of the apple with enzymes involved in the central nervous system (CNS), acetylcholinesterase, and butyrylcholinesterase, followed by binding affinity calculations using the AutoDock tool. The molecular docking results revealed that CID: 107905 exhibited the best interactions with AChE, with a binding affinity of -12.2 kcal/mol, and CID: 163103561 showed the highest binding affinity with BuChE, i.e., -11.2 kcal/mol. Importantly, it was observed that amino acid residue Trp286 of AChE was involved in hydrogen bond formation, Van Der Walls interactions, and Pi-Sigma/Pi-Pi interactions in the studied complexes. Moreover, the results of the Molecular Dynamics Simulation (MDS) analysis indicated interaction stability. This study shows that CID: 12000657 could be used as an AChE inhibitor and CID: 135398658 as a BuChE inhibitor to treat Alzheimer's disease and other neurological disorders.

Quest for selective MMP9 inhibitors: a computational approach

Matrix Metalloproteinases-9 (MMP-9) is one of the important targets that play a vital role in various diseases such as cancer, Alzheimer’s, arthritis, etc. Traditionally, MMP-9 inhibitors have been unable to achieve selectivity to get around this target; thereby, novel mechanisms such as inhibition of activated MMP-9 zymogen (pro-MMP-9) have been discovered. The JNJ0966 was one of the few compounds that attained the requisite selectivity by inhibiting the activation of MMP-9 zymogen (pro-MMP-9). Since JNJ0966, no other small molecules have been identified. Herein, extensive in silico studies were called upon to bolster the prospect of exploring potential candidates. The key objective of this research is to identify the potential hits from the ChEMBL database via molecular docking and dynamics approach. Protein with PDB ID: 5UE4, having a unique inhibitor in an allosteric binding pocket of MMP-9, was chosen for the study. Structure-based virtual screening and MMGBSA binding affinity calculations were performed, and five potential hits were finalized. Detailed analysis of the best-scoring molecules was performed with ADMET analysis and molecular dynamics (MD) simulation. All five hits outperformed JNJ0966 in the docking assessment, ADMET analysis, and molecular dynamics simulation. Accordingly, our research findings imply that these hits can be investigated for in vitro and in vivo studies against proMMP9 and might be explored as potential anticancer drugs. The outcome of our research might contribute in expediting the exploration of drugs that inhibits proMMP-9. Communicated by Ramaswamy H. Sarma

Synthesis and Biological Evaluation of New Fluorescent Probe BPN-01: A Model Molecule for Fluorescence Image-guided Surgery.

Fluorescence image-guided surgery (FIGS) can serve as a tool to achieve successful resection of tumour tissues during surgery, serving as a surgical navigator for surgeons. FIGS relies on the use of fluorescent molecules that can specifically interact with cancer cells. In this work, we developed a new model of fluorescent probe based on benzothiazole-phenylamide moiety featuring the visible fluorophore nitrobenzoxadiazole (NBD), namely BPN-01. This compound was designed and synthesised for potential applications in the tissue biopsy examination and ex-vivo imaging during FIGS of solid cancers. The probe BPN-01 exhibited favourable spectroscopic properties, particularly in nonpolar and alkaline solvents. Moreover, in vitro fluorescence imaging revealed that the probe appeared to recognise and be internalised in the prostate (DU-145) and melanoma (B16-F10) cancer cells, but not in the normal cells (myoblast C2C12). The cytotoxicity studies revealed that probe BPN-01 was not toxic to the B16 cells, suggesting excellent biocompatibility. Furthermore, the computational analysis showed that the calculated binding affinity of the probe to both translocator protein 18kDa (TSPO) and human epidermal growth factor receptor 2 (HER2) was considerably high. Hence, probe BPN-01 displays promising properties and may be valuable for visualising cancer cells in vitro. Furthermore, ligand 5 can potentially be labelled with NIR fluorophore and radionuclide, and serves as a dual imaging agent for in vivo applications.

Absolute binding affinities of phospholipids to Erwinia ligand-gated ion channel (ELIC) by streamlined alchemical free energy perturbations (SAFEP).

An increasing number of cryo-EM structures of membrane proteins contain putative lipid binding sites with partially resolved lipid densities. In principle, these densities might be identified by computing the binding free energies of candidate ligands by alchemical free energy perturbation (FEP). In practice, however, these systems have several challenging features including lipid flexibility, system heterogeneity, and low binding affinity. Each of these confounds the distinction between the bound and unbound state: flexible molecules have large accessible volumes in conformation space; heterogeneous environments complicate the unbound state; and open, low-affinity sites mean that a “bound” ligand may still have considerably higher entropy than more in a more traditional, high-affinity binding pocket. Our SAFEP method seeks to address these problems by defining a single collective variable to define the bound state. This distance-from-bound configuration (DBC) metric reliably classifies ligand-protein conformations as “bound” or “unbound.” SAFEP has been successfully applied to the computation of absolute binding affinities of cholesterol to three GPCRs and relative binding affinities of phospholipids to two mutants of ELIC based on structural data. We have extended SAFEP to the calculation of absolute binding affinities of phospholipids. This has required additional sampling of each state and refinement to the collective variables used, especially in the unbound state. While this is somewhat more computationally expensive than computing relative free energies, absolute affinities make functional questions more accessible and mitigate the error propagation inherent to relative binding affinities. It is our hope that these methods will aid in the interpretation of similar systems.

Consensus Algorithm for Calculation of Protein Binding Affinity using Multiple Models

The major histocompatibility complex (MHC) molecules, which bind peptides for presentation on the cell surface, play an important role in cell-mediated immunity. In light of developing databases and technologies over the years, significant progress has been made in research on peptide binding affinity calculation. Several in techniques have been developed to predict peptide binding to MHC class I. Most of the research on MHC Class I due to its nature brings better performance and more. Considering the use of different methods and different technologies, and the approach of similar methods on different proteins, a classification was created according to the binding affinity of protein peptides. For this classification, MHC Class I was studied using the MHCflurry, NetMHCPan, NetMHC, NetMHCCons and ssmpmbec. In these simulations conducted within the scope of this thesis, no overall superiority was observed between the models. It has been determined that they are superior to each other in various points. Getting the best results may vary depending on the multiple uses of models. The important thing is to recognize the data and act with the appropriate model. But even that doesn’t make a huge difference. Since the consensus approach is directly related to the models, the better the models, the better. Xix

ELECTRON WITHDRAWING GROUP EFFECT ON BIOLOGICAL ACTIVITIES OF PYRIMIDINE HYBRIDS AS POTENTIAL ANTI-MATRIX METALLOPROTEINASE-7

We investigated the effect of both electron donating group and e//lectron withdrawing group on biological activity of pyrimidine-based compounds as metalloproteinase-7 inhibitors and predicting a library of drug-like compounds with potent cytotoxicity using in silico approach. The selected compounds were optimized and subjected to both docking as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) analyzes. We observed that the addition of electron withdrawing group (–CF3) to the predicted pyrimidine-based compound induced a radical improvement in the hydrogen bond strength with Leu181 and Ala182 in matrix metalloproteinase-7. Also, communal orientation of 2-mercapto-4-(3-(trifluoromethyl)phenyl)-6-((4-(trifluoromethyl)phenyl)amino) pyrimidine-5-carbonitrile (PC10) and matrix metalloproteinase-7 showed improved binding tendency with calculated binding affinity value of −10.2 kcal mol-1 than other studied compounds. Our findings may open door for the design and development of library of efficient pyrimidine-based drug-like compounds as potential anti-cancer agents.

System truncation accelerates binding affinity calculations with the fragment molecular orbital method: A benchmark study.

The fragment molecular orbital (FMO) method is a fast quantum-mechanical method that divides systems into pieces of fragments and performs ab initio calculations. The system truncation enables further speed improvement. In this article, we systematically study the effects of system truncations on binding affinity calculations obtained with FMO in combination with either the polarizable continuum model (FMO/PCM) or in combination with the Møller-Plesset method (FMO-MP2). We have used five protein complexes with ligands of several charged states. The calculated binding energies of the size variants of the truncated system, including only a restricted number of atoms around the ligand, are compared to the energy obtained from a full system. The result shows that the systems could be truncated to a radius of 8Å from neutral ligands within an error of 0.7kcal/mol, and 12 Å from charged ligands within an error of 1.1kcal/mol for calculating the binding energy in solution.