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CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles. [ABSTRACT FROM AUTHOR]

Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently,N′-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as3a,3band3 hsignificantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative3ashowed a higher survival rate at anin vivomodel of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. Thein silicostudies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by3a, which was confirmed by tracking plasma levels of PGE2and TXB2through anin vitroenzyme immunoassay. Derivative3ashowed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases. [ABSTRACT FROM PUBLISHER]

Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer's disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q² = 0.757; SEcv = 0.493; R² = 0.937; SE = 0.251; R²pred = 0.659) presents high goodness-of-fit (R² > 0.9), as well as high internal (q² > 0.7) and external (R²pred > 0.5) predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors. [ABSTRACT FROM AUTHOR]

Recently, many efforts have been made to develop N-methyl- d-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives ( 1a- 1q), reported as N-methyl- d-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting ( R = 0.914) was able to explain 83.6% of the biological data variance ( R2 = 0.836), presented a satisfactory internal predictive ability ( Q2 = 0.609) and contained the descriptors (EHOMO, Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl- d-aspartic acid receptor antagonists. [ABSTRACT FROM AUTHOR]

Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied on a series of 54 2-arylbenzothiophene derivatives, synthesized by Grese and coworkers, based on raloxifene (an estrogen receptor-alpha antagonist), and evaluated as ERa ligands and as inhibitors of estrogen-stimulated proliferation of MCF-7 breast cancer cells. The conformations of each analogue, sampled from a molecular dynamics simulation, were placed in a grid cell lattice according to three trial alignments, considering two grid cell sizes (1.0 and 2.0 Å). The QSAR equations, generated by a combined scheme of genetic algorithms (GA) and partial least squares (PLS) regression, were evaluated by "leave-one-out" cross-validation, using a training set of 41 compounds. External validation was performed using a test set of 13 compounds. The obtained 4D-QSAR models are in agreement with the proposed mechanism of action for raloxifene. This study allowed a quantitative prediction of compounds' potency and supported the design of new raloxifene analogs. [ABSTRACT FROM AUTHOR]

Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive ( q2 above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases not yet studied. [ABSTRACT FROM AUTHOR]

Investigations on the photoprotection mechanisms of molecular sunscreens is critical to developing more efficacious sunscreen products. Molecular modeling has proved to be very helpful in understanding intrinsic properties of molecules that protect our skin from the harmful rays of the sun and gathering useful features to developing improved sunscreens. Herein the investigation focuses on the stereoelectronic properties related to photoprotection mechanisms of triazine and benzotriazole derivatives, important compound classes based on their physical-chemical properties, such as resonance and ultraviolet (UV) broad spectrum absorption (UVA and UVB). The method proved to be a valuable tool to reproduce the experimental UV absorption of a set of triazine and benzotriazole derivatives with compromise between the accuracy and the computational speed. All calculations were carried out considering only the isolated UV filter (in vacuum) and have provided a qualitative prediction and interpretation of absorption properties. The lowest band gap energy (E bg ), highest chemical potential (μ) and lowest chemical hardness (η) values were observed to the orthohydroxy substituted derivatives that are able to undergo excited-state proton transfer (ESPT), supporting the UVA absorption and resulting in excellent photostability. [ABSTRACT FROM AUTHOR]

Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC 50 for KLK1 The most active compound ( 10 ) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects. [ABSTRACT FROM AUTHOR]

• Montmorillonite (MMT) may play a very crucial role in modulating drug delivery of class II drugs of biopharmaceutical classification system, such as bromopride. • Bromopride was successfully intercalated in the sodium-MMT and the complex showed sustained release during performed assays. • This new bromopride sustained-release system showed an alternative to improve its pharmacological performance in therapeutic applications. • Molecular dynamics simulations showed the bromopride interactions to the montmorillonite layer. The drug delivery systems are an important strategy of pharmaceutical technology to modulate undesirable properties, increasing efficacy, and reducing the side effects of active pharmaceutical ingredients (API). The sustained release is a type of controlled-release system that provides a suitable drug level in the blood through a slow release rate. An interesting alternative to achieve a controlled release is the application of carrier materials such as polymers, cyclodextrins, and clays. Sodium montmorillonite (Na-MMT) is a biocompatible natural clay that allows the insertion of organic compounds in interlamellar space, owing to its high cation exchange capacity and large internal surface area. Bromopride (BPD) is an aminated compound with antiemetic properties classified as class II (low solubility, high permeability) of the Biopharmaceutical Classification System (BCS). Herein, the aim of the study was the development and investigation of a drug delivery system formed by intercalation of BPD with Na-MMT. The results indicate the successful intercalation of this API with the lamellar silicate, meanwhile, there was no evidence of BPD intercalation in organic montmorillonite. The Na-MMT/BPD molecular complex exhibits a sustained release in performed assays. Molecular dynamics simulations suggested that BPD molecules interact with the montmorillonite layer through ion-dipole interactions and also between BPD molecules, forming hydrogen bonds web into montmorillonite interlayer space. The new drug delivery system showed an alternative to achieve the BPD sustained release, which may improve its pharmacological performance in therapeutic applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: In this work we described the synthesis, the antileishmanial activity and the molecular modeling and structure–activity relationship (SAR) evaluations of a series of chalcone derivatives. Among these compounds, the methoxychalcones 2h, 2i, 2j, 2k and 2l showed significant antileishmanial activity (IC50 <10μM). Interestingly 2i (IC50 =2.7μM), 2j (IC50 =3.9μM) and 2k (IC50 =4.6μM) derivatives presented better antileishmanial activity than the control drug pentamidine (IC50 =6.0μM). Our SAR study showed the importance of methoxy di-ortho substitution at phenyl ring A and the relationship between the frontier orbital HOMO coefficients distribution of these molecules and their activity. The most active compounds 2h, 2i, 2j, 2k, and 2l fulfilled the Lipinski rule-of-five which theoretically is important for good drug absorption and permeation through biological membranes. The potential profile of 2j (IC50 =3.9μM and CC50 =216μM) pointed this chalcone derivative as a hit compound to be further explored in antileishmanial drug design. [Copyright &y& Elsevier]

Abstract: Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A–F (N = 47, q 2 = 0.736, r 2 = 0.860) and C–F (N = 47, q 2 = 0.753, r 2 = =0.900) were developed and validated by a combined GA-PLS approach, available in WOLF. Residues of the aromatic gorge (Tyr341 and Trp439) and catalytic triad (His447) are related to both equations showing the consistency of these models with the SAR. Based on those models we have proposed four new benzylpiperidine derivatives and predicted the pIC50 for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor. [Copyright &y& Elsevier]

Abstract: αIIbβ3 is an integrin that is involved in platelet adhesion and aggregation. This receptor may be inhibited by cysteine-rich peptides known as disintegrins. We isolated two disintegrins from Bothrops jararaca venom called jarastatin and jararacin. We evaluated the structural characteristics and the effects on human platelet aggregation of these disintegrins. Inhibitory profiles were compared to six distinct peptides synthesized based on their RGD hairpin loop primary sequences. Both jarastatin and jararacin inhibited ADP and thrombin induction. Conversely, none of the cyclic peptides showed high-quality activity in assays induced by ADP or thrombin. We constructed homology models for all of these molecules, and theoretically evaluated their interaction with the αIIbβ3 crystal structure using a molecular modeling approach. These results support the observations that the cyclic peptides had little effects, and also reinforce the observation that residues outside the disintegrin RGD sequence are required for interactions with receptor. [Copyright &y& Elsevier]