No / Decaprenylphosphoryl-b-d-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of benzothiazolylpyrimidine-5-carboxamides (7a–t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted aromatic benzaldehydes. These derivatives were evaluated for antitubercular activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H37Rv). Log P of these compounds was found to be between 2.0 and 3.0 making them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q2, q2_se and Pred_r2se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors. / Council of Scientific and Industrial Research

Kovalente Inhibition stellt einen effektiven Weg dar, die Verweildauer des Liganden innerhalb einer Bindetasche zu erhöhen. In dieser Arbeit wurden theoretische Methoden angewendet, um die Reaktivität und den nichtkovalenten Zustand vor der Reaktion zu modellieren. Im Rahmen einer Fallstudie zu Cathepsin K wurden nichtkovalente Modelle von kovalenten Inhibitoren generiert. Für verschiedene Komplexe aus Cathepsin K und einem kovalent gebundenem Liganden wurde der Zustand vor der Reaktion modelliert und dessen Stabilität im Rahmen einer klassischen MD-Simulation überprüft. Die Stabilität des Warheads in der Bindetasche hing hauptsächlich vom gewählten Protonierungszustand der katalytischen Aminosäuren ab. Für eine Reihe von Inhibitoren der ChlaDUB1 wurde ein Protokoll aus quantenmechanischen Rechnungen genutzt, um die Reaktivität verschiedener Warheads abzuschätzen. Die erhaltenen Aktivierungsenergien korrelierten mit experimentell bestimmten Raten zur Inaktivierung des Enzyms. Im Rahmen eines Wirkstoffdesign-Projektes zur Deubiquitinase USP28 wurden von unpublizierten Kristallstrukturen ausgehend erste Docking-Experimente durchgeführt. Es konnte gezeigt werden, dass ein literaturbekannter Inhibitor von USP28 mit einem Warhead so modifiziert werden kann, dass die reaktive Einheit in direkter Nachbarschaft zu einem Cystein positioniert wird. Für diese Warheads wurden ebenfalls quantenmechanische Rechnungen zur Bestimmung der Aktivierungsenergie durchgeführt. Um besser nachvollziehen zu können, warum bei einem Photoswitch-Inhibitor der Butyrylcholin-Esterase der cis-Zustand des Moleküls besser inhibiert als der trans-Zustand, wurde eine Docking-Studie des Zustandes vor der Reaktion durchgeführt. Es konnte ein qualitatives Modell aufgestellt werden, das zeigt, dass der trans-Zustand aufgrund seiner längeren Form mit wichtigen Aminosäuren am Eingang der Bindungstasche kollidiert. / Covalent inhibition is an effective way to increase the residence time of a ligand within the active site. In this work theoretical methods were used to model the reactivity and the noncovalent pre-reaction state. Noncovalent models of covalent inhibitors were generated as part of a case study of Cathepsin K. Several complexes of Cathepsin K and a covalently bound ligand were modeled in their state before the reaction, and their stability was assessed by classical molecular dynamics simulations. In most cases the warhead was positioned in close proximity to the catalytic unit, remaining there for up to several hundred nanoseconds. This stable positioning was largely dependent on the protonation state of the catalytic amino acids. To estimate the reactivity of a series of ChlaDUB1 inhibitors, a protocol of quantum mechanical calculations was adapted. The obtained activation energies correlated with experimentally obtained rate constants of enzyme inactivation. Using unpublished crystal structures, first design steps for the inhibition of the deubiquitinase USP28 were performed. Docking studies showed that modification of a literature-known inhibitor of USP28 with a warhead allowed to place this reactive unit close to a cysteine. Activation energies were also obtained for these structures via quantum mechanical calculations. To better rationalize the differences in inhibition between the cis- and trans-state of a photoswitch inhibitor of butyrylcholine esterase, a docking study of the noncovalent state was performed. The different ring conformers and stereochemical properties of the photoswitch were critical for a sensible model of the ligand. A qualitative model could be obtained which explains that the cis-isomer is more active than the trans-isomer due to a steric clash of the latter with amino acids at the entrance of the pocket.

Abstract Background: Over the last few years, the principle of cross-docking has prominently spreadthrough the companies in which they try hard to make their supply chain channels efficientand achieve higher demands of the society. Studies claimed that inventory management remains to be challenge for professionals of supply chain as long-term processing times may result in considerable financial losses for firms. Aim: This research aims to evaluate the effectiveness of Hub-and-Spoke cross-dockingstrategy in inventory management by understanding the impact, outcomes or efficacy of its implementation. Methodology: This research has adopted qualitative research method to generate extensive data and deep insights to underlying factors behind organizations' decisions and behavior on the implementation of cross-docking concept. The interviews have been chosen as the main data collection method of this research because it has been used successfully in order to produce rich and detailed information about the participants in the supply chain management.The total sample size of the participants is 10. For instance, the research conducted interviews via In-person, Zoom and WhatsApp video calls. The researcher recruited supply chain managers including companies’ representatives, supply chain practitioners, logistic managers,inventory managers and related stakeholders responsible for executing and overviewing inventory management approaches within their firms operating in Sweden. Thus, individuals can offer useful information related to supply planning, implementing and optimising cross-docking operations within their organisations. Findings and Conclusion: The research has, however, led to the impact of the organizational culture on the sustainable Hub-and-Spoke cross-docking strategy with the participants, all agreeing on the role that culture plays in shaping the structure of the strategy in the long-term. Finally, organizational culture was considered to be the cornerstone system,emphasizing the values of innovation, collaboration, transparency, and employee empowerment that serve as the driving force for its application. Participants highlighted the significance of facilitating discussions on various levels, recognizing the importance of collaborations and teams, establishing training and development systems, creating the culture of continuous improvement, and empowering employees as key measures utilized in dealing with the organizational culture challenges in cross-docking implementation and sustainability. KPIs for the cross-dock's level of success and effectiveness include order fulfillment rates,inventory turnover and customer satisfaction, compliance, employee satisfaction, operational efficiency, and the practice of ethical business conduct and corporate values. Thus, thisresearch proves the connection between the organizational culture and best productivity ,results of cross-docking. This makes it clear that a supportive environment is important for a continued performance in cross-docking operations.

Computationally driven drug design/discovery efforts generally rely on accurate assessment of the forces that guide the molecular recognition process. HINT (Hydropathic INTeraction) is a natural force field, derived from experimentally determined partition coefficients that quantifies all non-bonded interactions in the biological environment, including hydrogen bonding, electrostatic and hydrophobic interactions, and the energy of desolvation. The overall goal of this work is to apply the HINT-based atomic level description of molecular systems to biologically important proteins, to better understand their biochemistry – a key step in exploiting them for therapeutic purposes. This dissertation discusses the results of three diverse projects: i) structural modeling of human sphingosine kinase 2 (SphK2, a novel anticancer target) and binding mode determination of an isoform selective thiazolidine-2,4-dione (TZD) analog; ii) structural modeling of human cytomegalorvirus (HCMV) alkaline nuclease (AN) UL98 (a novel antiviral target) and subsequent virtual screening of its active site; and iii) explicit treatment of interfacial waters during protein-protein docking process using HINT-based computational tools. SphK2 is a key regulator of the sphingosine-rheostat, and its upregulation /overexpression has been associated with cancer development. We report structural modeling studies of a novel TZD-analog that selectively inhibits SphK2, in a HINT analysis that identifies the key structural features of ligand and protein binding site responsible for isoform selectivity. The second aim was to build a three-dimensional structure of a novel HCMV target – AN UL98, to identify its catalytically important residues. HINT analysis of the interaction of 5’ DNA end at its active site is reported. A parallel aim to perform in silico screening with a site-based pharmacophore model, identified several novel hits with potentially desirable chemical features for interaction with UL98 AN. The majority of current protein-protein docking algorithms fail to account for water molecules involved in bridging interactions between partners, mediating and stabilizing their association. HINT is capable of reproducing the physical and chemical properties of such waters, while accounting for their energetic stabilizing contributions. We have designed a solvated protein-protein docking protocol that explicitly models the Relevant bridging waters, and demonstrate that more accurate results are obtained when water is not ignored.

Idag sker många transporter med låg utnyttjandegrad vilket gör att transportkostnaden per produkt blir hög samtidigt som transporter har en negativ påverkan på miljön. Genom att konsolidera transporter kan utnyttjandegraden av transporterna öka. Ökad utnyttjandegrad kan även hjälpa företagen att gå mot cirkulär ekonomi där målet är att utnyttja resurserna maximalt. För små och medelstora företag kan det dock vara svårt att bygga upp samarbeten med andra företag. Dessa företag möter olika möjligheter och hinder vid implementering av transportkonsolidering, därför kommer denna studien identifiera vilka dessa är.Studien har genomförts i samarbete med 16 företag i Orust kommun och har visat att de största hindren vid transportkonsolidering är kundkrav, produktkrav och informationsdelning. Företagen upplevde att kundernas krav på korta ledtider skulle göra det svårt att samordna transporter med andra företag. Många företag upplevde även att produktkraven deras produkter ställer på transporterna skulle försvåra transportkonsolidering. Studien kunde dock visa att flera företag hade liknande produktkrav vilket möjliggör transportkonsolidering. En del företag ansåg att det saknades stöd och samarbete för den informationsdelning som krävs vid konsolidering.De främsta möjligheterna som identifierades är företagskulturen och viljan att gå mot en mer hållbar distributionskedja. Företagen som deltog i intervjuerna nämnde att de såg positivt på transportkonsolidering om det fanns ett sätt att enkelt samordna transporterna. De är även aktiva i Orust Kretsloppsakademi som arbetar för ett hållbart Orust vilket visar att det finns ett intresse av att bli mer hållbara. / Today, many transports are at a low rate of utilization. This means that shipping costs per product will be high and at the same time transports have a negative impact on the environment. Consolidating transports can increase the utilization rate for transports which minimizes costs and environmental impact. Increased utilization rates can also help companies move towards circular economics where the goal is to maximize their utilization of resources. However, for small and medium size companies it may be difficult to build up partnerships with other companies. These companies face different possibilities and obstacles in implementing transport consolidation, therefore this study will identify these.The study has been carried out in cooperation with 16 companies in Orust and has shown that the main obstacles to transport consolidation are customer requirements, product requirements and information sharing. The companies perceived that customer demand for short lead times would make it difficult to coordinate transport with other companies. Many companies also found that the product requirements of their products on transport would make transport consolidation difficult. However, the study showed that several companies had similar product requirements, which enables transport consolidation. Some companies also felt that there was no support and cooperation for the information sharing required for consolidation.The main opportunities identified were corporate culture and the desire to move towards a more sustainable distribution chain. The companies that participated in the interviews mentioned that they can see possibilities of transport consolidation if there was a way to easily coordinate transport. They are also active in the Orust Kretsloppsakademi that works for a sustainable Orust, which shows that there is an interest in becoming more sustainable.

Background: Many processes play a critical role in making non-manufacturing operations work as optimal as possible. One of these processes that is an important part of these activities is the goods flow process. If this process does not function effectively, this can affect the entire business, which in turn will lead to huge costs and lead times. It is therefore important that the flow of goods in the terminal works well because customers nowadays require that goods that they place an order have to be delivered as soon as possible. Purpose: The aim of the study is to find solutions for streamlining flow of incoming and outgoing goods, which will reduce unnecessary transport distances between goods reception and delivery ports, as well as finding a solution for lack of surface. Methodology: All necessary information has been collected by using qualitative and quantitative data and with the help of various types of interviews: semi-structured and unstructured, as well as participating in observations to initiate process mapping and find new terminal design. Subsequently, cost savings were achieved by comparing the new and old terminal design, after that calculations were performed to see how much surface use was made more efficient with movement of LKM stock. Conclusion: By analyzing incoming goods flow and changing port usage in the terminal, in other words by increasing the number of ports for a department and by distributing goods flow between ports in an optimal manner, goods flow efficiency can be achieved. Non-manufacturing operations work can improve its productivity by optimizing floor space usage and eliminating waste and defects which effect goods handling. / Bakgrund: Många processer spelar kritisk roll för att icke-tillverkande verksamheter ska fungera så optimalt som möjligt. En av dessa processer som utgör en viktig del i sådana verksamheter är godsflödeprocessen. Om denna process inte fungerar på ett effektivt sätt kan det påverka hela verksamheten som i sin tur kommer att leda till stora kostnader och ledtider. Det är därför viktigt att godsflödet i terminalen fungerar väl eftersom kunder nuförtiden ställer höga krav på att gods som de lägger en beställning på skall levereras så snabbt så möjligt. Syfte: Studiens syfte är att hitta lösningar för att effektivisera flödet av in- och utgående gods som i sin tur kommer att minska onödiga truckkörningar mellan godsmottagning och utleverans portar, samt att optimera golvyta användning i terminalen. Metod: All nödvändig information har samlats in genom att använda kvalitativa och kvantitativa data och med hjälp av olika typer intervjuer: semi-strukturerade och ostrukturerade, samt genom deltagande observationer för att initiera processkartläggning och designa ny terminallayout. Därefter räknades kostnadsbesparingen fram som uppnåddes genom att jämföra den nya och gamla terminaldesignen, efter detta utfördes beräkningar för att se hur mycket användning av golvyta effektiviserades med LKM lager förflyttning. Slutsats: Genom att analysera inkommande godsflöde och ändra portanvändning i terminalen, det vill säga utöka antal portar för en avdelning samt genom att fördela godsflöde mellan portar på ett optimalt sätt kan godsflödeeffektivisering åstadkommas. Icke-tillverkande verksamhet kan förbättra sin produktivitet genom att optimera golvyta användning och eliminering av slöserier och brister i godshanteringen.

Le docking moléculaire est une méthode permettant de prédire l'orientation d'une molécule donnée relativement à une autre lorsque celles-ci forment un complexe. Le premier algorithme de docking moléculaire a vu jour en 1990 afin de trouver de nouveaux candidats face à la protéase du VIH-1. Depuis, l'utilisation de protocoles de docking est devenue une pratique standard dans le domaine de la conception de nouveaux médicaments. Typiquement, un protocole de docking comporte plusieurs phases. Il requiert l'échantillonnage exhaustif du site d'interaction où les éléments impliqués sont considérées rigides. Des algorithmes de clustering sont utilisés afin de regrouper les candidats à l'appariement similaires. Des méthodes d'affinage sont appliquées pour prendre en compte la flexibilité au sein complexe moléculaire et afin d'éliminer de possibles artefacts de docking. Enfin, des algorithmes d'évaluation sont utilisés pour sélectionner les meilleurs candidats pour le docking. Cette thèse présente de nouveaux algorithmes de protocoles de docking qui facilitent la prédiction des structures de complexes protéinaires, une des cibles les plus importantes parmi les cibles visées par les méthodes de conception de médicaments. Une première contribution concerne l‘algorithme Docktrina qui permet de prédire les conformations de trimères protéinaires triangulaires. Celui-ci prend en entrée des prédictions de contacts paire-à-paire à partir d'hypothèse de corps rigides. Ensuite toutes les combinaisons possibles de paires de monomères sont évalués à l'aide d'un test de distance RMSD efficace. Cette méthode à la fois rapide et efficace améliore l'état de l'art sur les protéines trimères. Deuxièmement, nous présentons RigidRMSD une librairie C++ qui évalue en temps constant les distances RMSD entre conformations moléculaires correspondant à des transformations rigides. Cette librairie est en pratique utile lors du clustering de positions de docking, conduisant à des temps de calcul améliorés d'un facteur dix, comparé aux temps de calcul des algorithmes standards. Une troisième contribution concerne KSENIA, une fonction d'évaluation à base de connaissance pour l'étude des interactions protéine-protéine. Le problème de la reconstruction de fonction d'évaluation est alors formulé et résolu comme un problème d'optimisation convexe. Quatrièmement, CARBON, un nouvel algorithme pour l'affinage des candidats au docking basés sur des modèles corps-rigides est proposé. Le problème d'optimisation de corps-rigides est vu comme le calcul de trajectoires quasi-statiques de corps rigides influencés par la fonction énergie. CARBON fonctionne aussi bien avec un champ de force classique qu'avec une fonction d'évaluation à base de connaissance. CARBON est aussi utile pour l'affinage de complexes moléculaires qui comportent des clashes stériques modérés à importants. Finalement, une nouvelle méthode permet d'estimer les capacités de prédiction des fonctions d'évaluation. Celle-ci permet d‘évaluer de façon rigoureuse la performance de la fonction d'évaluation concernée sur des benchmarks de complexes moléculaires. La méthode manipule la distribution des scores attribués et non pas directement les scores de conformations particulières, ce qui la rend avantageuse au regard des critères standard basés sur le score le plus élevé. Les méthodes décrites au sein de la thèse sont testées et validées sur différents benchmarks protéines-protéines. Les algorithmes implémentés ont été utilisés avec succès pour la compétition CAPRI concernant la prédiction de complexes protéine-protéine. La méthodologie développée peut facilement être adaptée pour de la reconnaissance d'autres types d'interactions moléculaires impliquant par exemple des ligands, de l'ARN… Les implémentations en C++ des différents algorithmes présentés seront mises à disposition comme SAMSON Elements de la plateforme logicielle SAMSON sur http://www.samson-connect.net ou sur http://nano-d.inrialpes.fr/software. / Molecular docking is a method that predicts orientation of one molecule with respect to another one when forming a complex. The first computational method of molecular docking was applied to find new candidates against HIV-1 protease in 1990. Since then, using of docking pipelines has become a standard practice in drug discovery. Typically, a docking protocol comprises different phases. The exhaustive sampling of the binding site upon rigid-body approximation of the docking subunits is required. Clustering algorithms are used to group similar binding candidates. Refinement methods are applied to take into account flexibility of the molecular complex and to eliminate possible docking artefacts. Finally, scoring algorithms are employed to select the best binding candidates. The current thesis presents novel algorithms of docking protocols that facilitate structure prediction of protein complexes, which belong to one of the most important target classes in the structure-based drug design. First, DockTrina - a new algorithm to predict conformations of triangular protein trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) is presented. The method takes as input pair-wise contact predictions from a rigid-body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation (RMSD) test. Being fast and efficient, DockTrina outperforms state-of-the-art computational methods dedicated to predict structure of protein oligomers on the collected benchmark of protein trimers. Second, RigidRMSD - a C++ library that in constant time computes RMSDs between molecular poses corresponding to rigid-body transformations is presented. The library is practically useful for clustering docking poses, resulting in ten times speed up compared to standard RMSD-based clustering algorithms. Third, KSENIA - a novel knowledge-based scoring function for protein-protein interactions is developed. The problem of scoring function reconstruction is formulated and solved as a convex optimization problem. As a result, KSENIA is a smooth function and, thus, is suitable for the gradient-base refinement of molecular structures. Remarkably, it is shown that native interfaces of protein complexes provide sufficient information to reconstruct a well-discriminative scoring function. Fourth, CARBON - a new algorithm for the rigid-body refinement of docking candidates is proposed. The rigid-body optimization problem is viewed as the calculation of quasi-static trajectories of rigid bodies influenced by the energy function. To circumvent the typical problem of incorrect stepsizes for rotation and translation movements of molecular complexes, the concept of controlled advancement is introduced. CARBON works well both in combination with a classical force-field and a knowledge-based scoring function. CARBON is also suitable for refinement of molecular complexes with moderate and large steric clashes between its subunits. Finally, a novel method to evaluate prediction capability of scoring functions is introduced. It allows to rigorously assess the performance of the scoring function of interest on benchmarks of molecular complexes. The method manipulates with the score distributions rather than with scores of particular conformations, which makes it advantageous compared to the standard hit-rate criteria. The methods described in the thesis are tested and validated on various protein-protein benchmarks. The implemented algorithms are successfully used in the CAPRI contest for structure prediction of protein-protein complexes. The developed methodology can be easily adapted to the recognition of other types of molecular interactions, involving ligands, polysaccharides, RNAs, etc. The C++ versions of the presented algorithms will be made available as SAMSON Elements for the SAMSON software platform at http://www.samson-connect.net or at http://nano-d.inrialpes.fr/software.

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