Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring the enumeration of macrocyclic conformers before docking. Here, we characterize the performance of the method for handling macrocyclic compounds, which is implemented and the default behaviour for ligand preparation with our ligand preparation pipeline, Meeko. A pseudoatom is used to encode bond geometry and produce an anisotropic closure force for macrocyclic rings. This method is evaluated on a diverse set of small molecule and peptide macrocycles, ranging from 7- to 33-membered rings, showing little accuracy loss compared to rigid redocking of the X-ray macrocycle conformers. This suggests that for conformationally flexible macrocycles with unknown binding modes, this method can be effectively used to predict the macrocycle conformation.

Peptides mediate up to 40% of protein interactions, their high specificity and ability to bind in places where small molecules cannot make them potential drug candidates. However, predicting peptide–protein complexes remains more challenging than protein–protein or protein–small molecule interactions, in part due to the high flexibility peptides have. In this review, we look at the advances in docking, molecular simulations and machine learning to tackle problems related to peptides such as predicting structures, binding affinities or even kinetics. We specifically focus on explaining the number of docking programmes and force fields used in molecular simulations, so a prospective user can have an educated guess as to why choose one modelling tool or another to address their scientific questions.

Chikungunya virus (CHIKV) is a re-emerging pathogen of global importance. We attempted to gain an insight into the organisation, distribution and mutational load of the virus strains reported from different parts of the world. We describe transmission dynamics and genetic characterisation of CHIKV across the globe during the last 65 years from 1952 to 2017. The evolutionary pattern of CHIKV was analysed using the E1 protein gene through phylogenetic, Bayesian and Network methods with a dataset of 265 sequences from various countries. The time to most recent common ancestor of the virus was estimated to be 491 years ago with an evolutionary rate of 2.78 × 10−4 substitutions/site/year. Genetic characterisation of CHIKV strains was carried out in terms of variable sites, selection pressure and epitope mapping. The neutral selection pressure on the E1 gene of the virus suggested a stochastic process of evolution. We identified six potential epitope peptides in the E1 protein showing substantial interaction with human MHC-I and MHC-II alleles. The present study augments global epidemiological and population dynamics of CHIKV warranting undertaking of appropriate control measures. The identification of epitopic peptides can be useful in the development of epitope-based vaccine strategies against this re-emerging viral pathogen.

Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis.

Autonomous docking is a focus of research in the field of self-assembly robots. Navigation is a significant stage in the process of autonomous docking between two robotic modules; it determines the efficiency of docking and even the success and failure of the docking task. In most cases, it is too difficult to simultaneously satisfy both linear and angular displacement constraints in a single dynamic numerical computation process. In the present paper, the navigation process is divided into two stages: first, the angular displacement constraint is satisfied, and then the linear displacement condition is fulfilled. In this way, the constraints are loosened and the difficulty of numerical computation is thereby effectively reduced. This two-stage docking navigation model is the main contribution of the present work. By taking the non-holonomic nature of the navigation behavior into consideration, both kinematic and dynamic analyses are performed, and the voltage data of the DC motors required by the two-stage docking navigation are obtained. Finally, docking navigation experiments are completed on a self-assembly modular robot named Sambot. It is verified that the present two-stage strategy is effective in controlling the docking navigation process.

The effect of tail docking on metabolizable energy requirements and carcass characteristics was studied using 80 weaned entire Awassi male lambs. Docking was performed within 3 days of birth and lambs were weaned at 90 days old. Docked and undocked lambs were randomly allocated to four groups, individually penned and offered different amounts of a pelleted concentrate diet. The pelleted diet was estimated to contain 11·8 MJ of metabolizable energy (ME) and 182 g of crude protein (CP) per kg dry matter (DM). Lambs on the high levels of intake were slaughtered at a target weight of approximately 45 kg. Other lambs were maintained on the diet for 149 days before being slaughtered. The right sides of all carcasses were cut into standardized commercial cuts then dissected into muscle, fat and bone. The soft tissue was pooled and analysed for DM, C P, ash and fat. Prediction of live-weight gain (LWG) and empty body gain for a given ME intake (MEI) was made using the growth and MEI data. MEI was expressed as MJ per kg metabolic body weight (M 0·75) per day. Tail docking had no effect (P > 0·05) on lamb growth from birth to weaning. During the post-weaning growth period, LWG and empty body gain were significantly higher (P < 0·05) for undocked lambs than docked lambs, at feeding levels between 0·31 and 0·52 MJ/kg M 0·75 per day and similar (P > 0·05) at high levels of intakes (between 0·74 and 1·1 MJ/ kg M 0·75 per day). Hot and cold carcass weights were similar (P > 0·05) for the two groups. Differences in empty body weight and fleece-free empty body weight were significant (P < 0·05) only for the 0·443 to 0·522 MJ/kg M 0·75 per day level of ME intake. Predicted ME requirements were higher for docked lambs for an estimated LWG between 0 and 100 g/day and lower for higher LWG (125 to 225 g/day). Docking had no effect (P > 0·05) on food conversion efficiency (FCE). Carcasses from docked lambs had significantly lower (P < 0·001) internal plus tail fat. Pooled soft tissue excluding tail fat, for the undocked lambs contained significantly more (P < 0·01) protein, less (P < 0·001) fat, higher (P < 0·01) moisture and similar (P > 0·05) ash content.

Metabotropic glutamate receptors (mGluRs) belong to the family 3 of G-protein-coupled receptors. On these proteins, agonist binding on the extracellular domain leads to conformational changes in the 7-transmembrane domains required for G-protein activation. To elucidate the structural features that might be responsible for such an activation mechanism, we have generated models of the amino terminal domain (ATD) of type 4 mGluR (mGlu4R). The fold recognition search allowed the identification of three hits with a low sequence identity, but with high secondary structure conservation: leucine isoleucine valine-binding protein (LIVBP) and leucine-binding protein (LBP) as already known, and acetamide-binding protein (AmiC). These proteins are characterized by a bilobate structure in an open state for LIVBP/LBP and a closed state for AmiC, with ligand binding in the cleft. Models for both open and closed forms of mGlu4R ATD have been generated. ACPT-I (1-aminocyclopentane 1,3,4-tricarboxylic acid), a selective agonist, has been docked in the two models. In the open form, ACPT-I is only bound to lobe I through interactions with Lys74, Arg78, Ser159, and Thr182. In the closed form, ACPT-I is trapped between both lobes with additional binding to Tyr230, Asp312, Ser313, and Lys317 from lobe II. These results support the hypothesis that mGluR agonists bind a closed form of the ATDs, suggesting that such a conformation of the binding domain corresponds to the active conformation.

The ecdysone receptor (ECR), a nuclear transcription factor controlling insect development, is a novel target for insecticides such as dibenzoylhydrazines with low environmental and toxicological impacts. To understand the high selectivity of such synthetic molecules toward ECR, two homology models of the Chironomus tentans ECR ligand-binding domain (LDB) have been constructed by taking as templates the known LBD crystal structures of the retinoic acid and vitamin D receptors. Docking of 20-hydroxyecdysone (20E) and dibenzoylhydrazines to the receptor suggests a novel superposition of the natural and synthetic molecules; the N-tert-butyl substituent of the dibenzoylhydrazines extends significantly beyond the 20E volume. Our ECR–LBD protein models rationalize how 20E and dibenzoylhydrazines interact with the ligand-binding pocket. The homology model complexes provide new insights that can be exploited in the rational design of new environmentally safe insecticides.

The relationship between the structure of a free ligand in solution and the structure of its bound form in a complex is of great importance to the understanding of the energetics and mechanism of molecular recognition and complex formation. In this study, we use a structure-based thermodynamic approach to study the dissociation of the complex between the toxin microcystin-LR (MLR) and the catalytic domain of protein phosphatase-1 (PP-1c) for which the crystal structure of the complex is known. We have calculated the thermodynamic parameters (enthalpy, entropy, heat capacity, and free energy) for the dissociation of the complex from its X-ray structure and found the calculated dissociation constant (4.0 × 10−11) to be in excellent agreement with the reported inhibitory constant (3.9 × 10−11). We have also calculated the thermodynamic parameters for the dissociation of 47 PP-1c:MLR complexes generated by docking an ensemble of NMR solution structures of MLR onto the crystal structure of PP-1c. In general, we observe that the lower the root-mean-square deviation (RMSD) of the docked complex (compared to the X-ray complex) the closer its free energy of dissociation (ΔG°d) is to that calculated from the X-ray complex. On the other hand, we note a significant scatter between the ΔG°d and the RMSD of the docked complexes. We have identified a group of seven docked complexes with ΔG°d values very close to the one calculated from the X-ray complex but with significantly dissimilar structures. The analysis of the corresponding enthalpy and entropy of dissociation shows a compensation effect suggesting that MLR molecules with significant structural variability can bind PP-1c and that substantial conformational flexibility in the PP-1c:MLR complex may exist in solution.

The histological characteristics of the skin of docked and undocked fat-tailed sheep were studied at 15-day intervals between birth and 90 days of age, then every 30 days until 180 days and every 3 months until 1 year of age. Data presented in this paper were recorded at birth, 30, 60, 120,180 and 360 days of age. The fleece characteristics were studied at 1·0,1·5 and 2·0 years of age.

The skin structure was similar in docked and undocked Rahmani sheep and did not differ from that of other breeds of sheep.

The effect of docking was significant at most ages of the study on internal diameter of primary follicles and on the external and internal diameters of secondary and on average diameters of wool follicles (P < 0·05). The effect of docking was highly significant on each of staple length and wool diameter.