Predicting liposome formulations by the integrated machine learning and molecular modeling approaches

Liposome is one of the most widely used carriers for drug delivery because of the great biocompatibility and biodegradability.Due to the complex formulation components and preparation process,formulation screening mostly relies on trial-and-error process with low efficiency.Here liposome formulation prediction models have been built by machine learning(ML)approaches.The important parameters of liposomes,including size,polydispersity index(PDI),zeta potential and encapsulation,are predicted individually by optimal ML algorithm,while the formulation features are also ranked to provide important guidance for formulation design.The analysis of key parameter reveals that drug molecules with logS[-3,-6],molecular complexity[500,1000]and XLogP3(≥2)are priority for preparing liposome with higher encapsulation.In addition,naproxen(NAP)and palmatine HCl(PAL)represented the insoluble and water-soluble molecules are prepared as liposome formulations to validate prediction ability.The consistency between predicted and experimental value verifies the satisfied accuracy of ML models.As the drug properties are critical for liposome particles,the molecular interactions and dynamics of NAP and PAL liposome are further investigated by coarse-grained molecular dynamics simulations.The modeling structure reveals that NAP molecules could distribute into lipid layer,while most PAL molecules aggregate in the inner aqueous phase of liposome.The completely different physical state of NAP and PAL confirms the importance of drug properties for liposome formulations.In summary,the general prediction models are built to predict liposome formulations,and the impacts of key factors are analyzed by combing ML with molecular modeling.The availability and rationality of these intelligent prediction systems have been proved in this study,which could be applied for liposome formulation development in the future.

A SARS-CoV-2 neutralizing antibody discovery by single cell sequencing and molecular modeling

Although vaccines have been developed,mutations of SARS-CoV-2,especially the dominant B.1.617.2(delta)and B.1.529(omicron)strains with more than 30 mutations on their spike protein,have caused a significant decline in prophylaxis,calling for the need for drug improvement.Antibodies are drugs preferentially used in infectious diseases and are easy to get from immunized organisms.The current study combined molecular modeling and single memory B cell sequencing to assess candidate sequences before experiments,providing a strategy for the fabrication of SARS-CoV-2 neutralizing antibodies.A total of 128 sequences were obtained after sequencing 196 memory B cells,and 42 sequences were left after merging extremely similar ones and discarding incomplete ones,followed by homology modeling of the antibody variable region.Thirteen candidate sequences were expressed,of which three were tested positive for receptor binding domain recognition but only one was confirmed as having broad neutralization against several SARS-CoV-2 variants.The current study successfully obtained a SARS-CoV-2 antibody with broad neutralizing abilities and provided a strategy for antibody development in emerging infectious diseases using single memory B cell BCR sequencing and computer assistance in antibody fabrication.

Characterization of Gallic Acid Interaction with Human Serum Albumin by Spectral and Molecular Modeling Methods

The binding of drugs with human serum albumin（HSA） is a crucial factor influencing the distribution and bioactivity of drugs in the body.To understand the action mechanisms between gallic acid（GA,3,4,5-trihydroxybenzoic acid） and HSA,the binding of GA with HSA was investigated by a combined experimental and computational approach.The fluorescence properties of HSA and the binding parameters of GA collectively indicate that the binding is characterized by static quenching mechanism at one high affinity binding site.According to the estimated molecular distance between the donor（HSA） and the acceptor（GA）,the binding is related to the fluorescence resonance energy transfer.As indicated by the thermodynamic parameters,hydrophobic interaction plays a major role in the GA-HSA complex.Further,the experimental results reveal that GA is bound in the large hydrophobic cavity of subdomain IIA in the site I of HSA,which is well approved by molecular docking.

Host-guest interaction of β-cyclodextrin with isomeric ursolic acid and oleanolic acid:physicochemical characterization and molecular modeling study

Ursolic acid(UA) and oleanolic acid(OA) are insoluble drugs. The objective of this study was to encapsulate them into β-cyclodextrin(β-CD) and compare the solubility and intermolecular force of β-CD with the two isomeric triterpenic acids. The host-guest interaction was explored in liquid and solid state by ultraviolet-visible absorption,1H NMR, phase solubility analysis, and differential scanning calorimetry, X-ray powder diffractometry, and molecular modeling studies. Both experimental and theoretical studies revealed that β-CD formed 1: 1 water soluble inclusion complexes and the complexation process was naturally favorable. In addition, the overall results suggested that ring E with a carboxyl group of the drug was encapsulated into the hydrophobic CD nanocavity. Therefore, a clear different inclusion behavior was observed, and UA exhibited better affinity to β-CD compared with OA in various media due to little steric interference, which was beneficial to form stable inclusion complex with β-CD and increase its water solubility effectively.

Synthesis, Spectroscopic, Molecular Modeling and Anti-Fungal Studies of Some Divalent Metal Complexes of 4-Hydroxyacetophenone Isonicotinoyl Hydrazone

A novel ligand N-4-hydroxyacetophenone isonicotinoyl hydrazone and its manganese(II) and nickel(II) metal complexes have been synthesized. The synthesized Schiff base and its metal complexes have been characterized by physical state determination, melting point and solubility measurements in different solvents, infrared, proton nuclear magnetic resonance, mass spectrometric and powder X-ray spectroscopic techniques. The thermal properties of the prepared compounds were obtained from TG/DTG measurements. On the basis of the analytical techniques, the ligand was found to be bidentate in nature coordinating to the metal ions through the azomethine nitrogen and carbonyl oxygen atoms leading to distorted octahedral geometries of the metal complexes which were modeled using MM2 force field. The ligand and its metal(II) complexes were evaluated for antifungal activity against Aspergillus fumigatus, Aspergillus niger, Candida albicans and Rhizopus stolonifera. The antifungal evaluation results revealed an enhanced activity upon coordination of the ligand with the metal(II) ions. The activity of the metal complex to the tested fungal strains was in the order Ni(II) > Mn(II).

Structural analysis and molecular modeling of twoantitrichosanthin IgE clones from phage antibody library

Recently we constructed a murine IgE phage surfacedisplay library and screened out two IgE (Fab) cloneswith specific binding activity to Trichosanthin (TCS). Inthis work, the Vε and Vκ genes of the two clones weresequenced and their putative germline gene usages werestudied. On the basis of the known 3D structure of Trichosanthin and antibody, molecular modeling was carriedout to study the antigen-antibody interaction. The possible antigenic determinant sites on the surface of TCSrecognized by both the clones were analyzed, and the reaction forces between TCS and two Fab fragments werealso analyzed respectively.

Inclusion Property and Molecular Modeling of Calix[4]arene Derivatives

The inclusion properties of two calix[4]arene derivatives 5,11,17,23 tetra tert butyl 25, 27 bis (isopropyl carbamoyl methoxy) 26,28 diundecenyloxy calix[4]arene (C[4]A) and 25,27 dibutoxy 5,11,17,23 tetra tert butyl 26,28 diundecenyloxy calix[4]arene (C[4]B) were studied by gas chromatographic method. It was found that C[4]A could form inclusion complexes with benzene, toluene, methanol and ethanol while C[4]B could only form inclusion complex with methanol, which might be due to the different conformations of C[4]A and C[4]B. Molecular modeling showed that CH/π and OH/π interactions played important roles in the forming of inclusion complexes.

Molecular modeling study of the effect of base methylation on internal interactions and motions in DNA and implication to B-Z conformation change

Methylation in the bases of DNA is known to induce B-Z conformation change. In this work, molecular mechanics and normal mode analysis are used to probe how certain methylation affects the internal interactions and thermodynamic motions in the DNA double helixes in both B and Z conformations, and its implication to B-Z conformation change. By molecular modeling with Insight II, two cases involving cytosine C5 and guanine C8 methylation on both B and Z-form DNA duplex d(CGCGCG)2 are studied in comparison with the corresponding unmethylated duplexes. The internal interaction energies computed based on a molecular mechanics force field and the entropies due to internal motions computed according to a normal mode analysis are in fare agreement with respective observed thermodynamic quantities. The analysis on the computed individual energy terms suggests that the observed B-Z conformation change induced by methylation is primarily driven by enthalpic factors. A combination of changes in Van der Waals interaction, electrostatic interaction and hydrogen bonding likely contributes to the change of enthalpy that favors Z-conformation in the methylated states.

Prediction of antigenic determinants of trichosanthin by molecular modeling

The antigenic determinants of trichosanthin were predicted by molecular modeling. First, the threedimensional structure model of the antigen-binding fragment of anti-trichosanthin immunoglobulin E was built on the basis of its amino-acid sequence and the known three-dimensional structure of an antibody with similar sequence. Secondly, the preferable antigen-antibody interactions were obtained based on the known three-dimensional structure of trichosanthin and of the hypervariable regions of anti-trichosanthin immunoglobulin E. Two regions in the molecular surface of trichosanthin were found to form extensive interactions with the hypervariable regions of the antibody and have been predicted to be the possible antigenic determinants: one is composed of two polypeptide segments, Ile201-Glu210 and Ile225-Asp229, which are close to each other in the three-dimensional structure; and the other is the segment Lys173-Thr178. The former region seems to be the more reasonable antigenic determinant than the latter one.

Molecular modeling of alkaloids bouchardatine and orirenierine binding to sirtuin-1(SIRT1)

Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functions as an activator of proteins adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)and sirtuin 1(SIRT1).We used molecular modeling to investigate the SIRT1-binding capacity of compound 1 and various structural analogues,such as orirenierine A(2)and orirenierine B(3)isolated from the medicinal plant Oricia renieri.Methods We investigated the binding to human SIRT1(hSIRT1)of 25 natural products including theβ-indoloquinazoline alkaloids 1−3 and analogues,in comparison with the reference product sirtinol(R and S isomers).A sirtinol binding model was elaborated starting from the closed and open state conformations of the catalytic domain of hSIRT1(PDB structures 4KXQ and 4IG9).For each compound bound to SIRT1,the empirical energy of interaction(ΔE)was calculated and compared to that of sirtinol.Results In our model,compound 1 was found to bind modestly to the sirtinol site of SIRT1.In contrast,the presence of a phenolic OH group at position 7 on the quinazolinone moiety conferred a much higher binding capacity.Compound 2 provided SIRT1 protein complexes as stable as those observed with sirtinol.The replacement of the hydroxy substituent(2)with a methoxy group(3)reduced the SIRT1 binding capacity.Other SIRT1-binding natural products were identified,such as the alkaloids orisuaveolines A and B.Structure-binding relationships were discussed.Conclusion The study underlines the capacity of β-indoloquinazoline alkaloids to interact with SIRT1.This deacetylase enzyme could represent a molecular target for the alkaloid 2.This compound merits further attention for the design of drugs active against SIRT1-dependent pathologies.

Thermal,infrared spectroscopy and molecular modeling characterization of bone:An insight in the apatite-collagen type I interaction

An insight into the interaction of collagen type I with apatite in bone tissue was performed by using differential scanning calorimetry, Fourier transform infrared spectroscopy, and molecular modeling. Scanning electron microscopy shows that bone organic content incinerate gradually through the different temperatures studied. We suggest that the amide regions of the type I collagen molecule (mainly C=O groups of the peptide bonds) will be important in the control of the interactions with the apatite from bone. The amide I infrared bands of the collagen type I change when interacting to apatite, what might confirm our assumption. Bone tissue results in a loss of thermal stability compared to the collagen studied apart, as a consequence of the degradation and further combustion of the collagen in contact with the apatite microcrystals in bone. The thermal behavior of bone is very distinctive. Its main typical combustion temperature is at 360°C with a shoulder at 550°C compared to the thermal behavior of collagen, with the mean combustion peak at ca. 500°C. Our studies with molecular mechanics (MM+ force field) showed different interaction energies of the collagen-like molecule and different models of the apatite crystal planes. We used models of the apatite (100) and (001) planes;additional two planes (001) were explored with phosphate-rich and calcium-rich faces;an energetic preference was found in the latter case. We preliminary conclude that the peptide bond of collagen type I is modified when the molecule interacts with the apatite, producing a decrease in the main peak from ca. 500°C in collagen, up to 350°C in bone. The combustion might be related to collagen type I, as the ΔH energies present only small variations between mineralized and non-mineralized samples. The data obtained here give a molecular perspective into the structural properties of bone and the change in collagen properties caused by the interaction with the apatite. Our study can be useful to understand the biological synthesis of minerals as well as the organic-inorganic interaction and the synthesis of apatite implant materials.

Molecular Modeling and Synthesis of Ethyl Benzyl Carbamates as Possible Ixodicide Activity

Carbamates are molecules that have different types of biological activities and provide a particular chemical control against ticks. The new structures of the proposed compounds were optimized and synthetized respectively, through a molecular model using the methods:PM3, HF and DFT applying the B3LYP functional, with the basis 6-31+G(d) and 6-311+G(d,p), BVP86 and PBEPBE with 6-31+G(d) and the vibrational frequencies computed. These calculated frequencies were compared with the experimental ones to determine the most accurate level of theory for the prediction of vibrational frequencies of the compounds. The best results were obtained through HF/631+G(d). Additionally, we report a modification to obtain this type of compounds, and based on the amino-dehalogenation of ethyl chloroformate, different benzyl ethyl carbamates were synthesized modifying the base molecule. The performances obtained were compared to others already reported. The methodology used allowed us to synthesize new carbamates using benzylamine derivatives through a modification on the basic catalysis of the addition-elimination reaction.

Two alkaloids as α-amylase inhibitors: enzyme kinetics and molecular modeling investigations

In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal-G2-α-CNP）. We, for the first time, provided kinetic report and detailed inhibitory effects of both compounds on PPA. Lineweaver-Burk plot revealed that the inhibition was a mixed-noncompetitive type, and only one molecule of inhibitor bound to the enzyme or to the enzyme-substrate complex. Kinetic constants calculated from secondary plots were in millimole range. Dissociation constants of enzyme-inhibitor complex （KEI） were 0.9 mM and 3.5 mM, respectively. Moreover, dissociation constants of enzyme-inhibitor-substrate complex （KESI） were 0.04 mM and 0.31 mM, respectively. These data indicated that the inhibition was more inclined to competitive to Gal-G2-α-CNP hydrolysis. Further molecular docking study manifested that hydrogen bonding formed between acarbose and aspartic acid （Asp300）, histidine （His305） and glycine （Gly3-6）, while hydrogen bonding was observed between chelidonine and glutamic acid （Glu233）, lysine （Lys200） and His305. In addition, rutaecarpine had only one hydrogen bond with Lys200. Our data indicated that chelidonine and rutaecarpine were two promising drug candidates, and chelidonine possessed stronger inhibitory effect compared with rutaecarpine.

Molecular modeling on Zn(II) binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes

Aggregation of the amyloid b-peptide (A b) into insoluble fibrils is a key pathologi-cal event in Alzheimers disease. Zn(II) ion induces significant Ab aggregation at nearly physio-logical concentrations in vitro. In order to explore the induce mechanism, the possible binding modes of Zn(II) in Ab peptide are studied by molecular modeling method. First, the Ab species containing 1,2,4 and 12 peptides are established respectively. And next a Zn(II) ion is manually hold the different sits of the Ab species based on the experimental data and subsequently the coordinate atom and number are assigned. Finally, the optimum binding site is found by the system energy minimization. Modeling results show that in soluble Zn(II) complex, Nt of imidazole ring of His14, O of carbonyl of main-chain, and two O of water occupy the four ligand positions of the tetrahedral complex; in the aggregation of Ab, the His13(Nt)-Zn(II)-His14(Nt) bridges are formed by Zn(II) cross-linking action. Therefore, the possible Zn(II) binding mode obtained by the studies will be helpful to reveal the form mechanism of pathogenic aggregates in brain.

Molecular modeling of the inhibitory mechanism of copper(II) on aggregation of amyloidβ-peptide

Aggregation of amyloid ?-peptide (A?) into insoluble fibrils is a key pathological event in Alzheimer’s disease (AD). Under certain conditions, Cu(II) exhibits strong inhibitory ef-fect on the Zn(II)-induced aggregation, which occurs significantly even at nearly physiological concentrations of zinc ion in vitro. Cu(II) is considered as a potential factor in the normal brain preventing A? from aggregating. The possible mechanism of the inhibitory effect of Cu(II) is in-vestigated for the first time by molecular modeling method. In the mono-ring mode, the Y10 residue promotes typical quasi-helix conformations of A?. Specially, [Cu-H13(Np)-Y10(OH)] complex forms a local 3.010 helix conformation. In the multi-ring mode, the side chains of Q15 and E11 residues collaborate harmoniously with other chelating ligands producing markedly low energies and quasi-helix conformations. [Cu-3N-Q15(O)-E11(O1)] and [Cu-H13(Np)-Y10(OH)] complex with quasi-helix conformations may prefer soluble forms in solution. In addition, hydro-gen-bond interactions may be the main driving force for A? aggregation. All the results will pro-vide helpful clues for an improved understanding of the role of Cu(II) in the pathogenesis of AD and contribute to the development of an “anti-amyloid” therapeutic strategy.

Biophysical studies of the interaction between a triazole derivative and bovine serum albumin by multi-spectroscopic and molecular modeling methods

The interaction between 3-thiol-4-(2,4-dichlorobenzylideneamino)-5-methyl-4H-1,2,4-triazole (CBTZ) and bovine serum albumin (BSA) under physiological conditions was investigated by fluorescence,UV-vis absorption and circular dichroism (CD) spectroscopy as well as molecular modeling methods. The result of fluorescence experiment indicates the static quenching as a result of the formation of the CBTZ-BSA complex. The binding constants (Ka) at different temperatures were calculated according to the modified Stern-Volmer equation. The enthalpy change (-H) and entropy change (-S) were determined based on the van′t Hoff equation. Both negative-H and-S indicated that van der Waals and hydrogen-bonding forces were the dominant intermolecular forces to stabilize the CBTZ-BSA complex. Site marker competitive replacement experiments demonstrated that binding of CBTZ to BSA primarily took place in sub-domain IIA (Sudlow's site I). The binding distance (r = 7.2 nm) between CBTZ and the tryptophan residue of BSA was estimated according to the theory of fluorescence resonance energy transfer (FRET). The conformational studies by circular dichroism (CD) and three-dimensional fluorescence spectroscopy showed that the presence of CBTZ induced minor changes of the secondary structure of BSA. Molecular modeling study further confirmed the binding mode obtained experimentally.

Molecular Modeling and Docking of Mannose-binding Lectin from Lycoris radiata

Lycoris radiata mannose-binding lectin（LRL） is a protein which binds mannose residues specifically. The maturation peptide and three mannose-binding domains（residues 49-57, 80-88 and 113--121） of LRL were identified by sequence analysis. The 3D structure of LRL constructed by homology modeling shaped a flstular triangular prism. Three flanks of the prism are mainly composed of β-sheets and each flank has a mannose-binding domain. According to the docking and dynamics simulation, the bindings of residues 49--57 and 80--88 with mannose are more stable than that of residues 113--121 with it. The key residues for binding mannose are Gin80, Asp82, Ash84 and Tyr88. The study preliminarily analyzed the interaction sites and mechanism of LRL with mannoses, which could be useful for the study on insect-resistance and related drug discovery of LRL.

Study of STAT3 G-quadruplex folding patterns by CD spectroscopy and molecular modeling

The G-quadruplexes formed from G-rich strands in the telomere and oncogene-promoter regions are regarded as new promising targets in the cancer therapy.A G-quadruplex in the downstream flanking region of the signal transducer and activator of transcription 3（STAT3） gene was explored.Its folding patterns were proposed to be 3：2：2 and 3：3：1 loop isomers by the mutation analysis by CD spectroscopy.The structures were constructed and refined by molecular modeling method.

Buildingcrystal structures ofconjugatedpolymersthrough X-ray diffraction and molecular modeling

Crystal structure of conjugated molecules and polymers is fundamentally critical to understand their multilevel microstructures,carrier transport,and diverse functions.However,to determine the crystal structure of conjugated polymers is a significant challenge,mainly due to the poor crystallinity,weak diffraction,and instability under high-energy radiation.Here,we build the possible crystal structures of eight typical conjugated polymers,covering several widely used molecular segments in organic optoelectronics.We model the packing structures of these seed polymers based on synchrotron X-ray diffractions and molecular simulations.These crystal structures provide a new platform to predict the packing structures of more related polymer systems,extending the molecular scope.Based on this polymer crystal structure database,the multiscale microstructures and charge transport properties of conjugated polymers can be predicted before experiments.This study sets up a polymer crystal structure database to eliminate the current trial-and-error approaches and accelerating the design of high-performance conjugated polymers.

Synthesis and molecular modeling study of Cu(Ⅱ) complexes derived from 2-(diphenylmethylene)hydrazinecarbothioamide derivatives with cholinesterase inhibitory activities

Thiosemicarbazones of 2-amino-5-chlorobenzophenone and 3-aminobenzophenone （L1-La） have been synthesized and their Cu（II） complexes （1-4） were afforded via coordination with cupric chloride. All these compounds were characterized by UV-vis and lR spectroscopy together with CHN elemental analysis. NMR spectroscopy was also applied to characterize the ligands. In vitro cholinesterase inhibitory assays for the complexes （1-4） showed ICso values less than 10 ~molJL, with complex 1 exhibiting the most activity, ICso = 2.15 ~molJL and 2.16 i^molJL for AChE and BuChE, respectively. Molecular modeling simulation revealed the binding interaction template for complex I with the AChE and BuChE receptors. In DPPH assay, the complexes also showed more in vitro antioxidant activities in comt）arison tn their narent li^ands.