An Efficient Implementation of the Nwat-MMGBSA Method to Rescore Docking Results in Medium-Throughput Virtual Screenings

Nwat-MMGBSA is a variant of MM-PB/GBSA based on the inclusion of a number of explicit water molecules that are the closest to the ligand in each frame of a molecular dynamics trajectory. This method demonstrated improved correlations between calculated and experimental binding energies in both protein-protein interactions and ligand-receptor complexes, in comparison to the standard MM-GBSA. A protocol optimization, aimed to maximize efficacy and efficiency, is discussed here considering penicillopepsin, HIV1-protease, and BCL-XL as test cases. Calculations were performed in triplicates on both classic HPC environments and on standard workstations equipped by a GPU card, evidencing no statistical differences in the results. No relevant differences in correlation to experiments were also observed when performing Nwat-MMGBSA calculations on 4 or 1 ns long trajectories. A fully automatic workflow for structure-based virtual screening, performing from library set-up to docking and Nwat-MMGBSA rescoring, has then been developed. The protocol has been tested against no rescoring or standard MM-GBSA rescoring within a retrospective virtual screening of inhibitors of AmpC \u3b2-lactamase and of the Rac1-Tiam1 protein-protein interaction. In both cases, Nwat-MMGBSA rescoring provided a statistically significant increase in the ROC AUCs of between 20 and 30%, compared to docking scoring or to standard MM-GBSA rescoring

Исследование методом сетевой фармакологии и молекулярного докинга для выявления потенциальной противораковой активности морских цитотоксинов — осциллатоксинов D, E, и F

Oscillatoxins (OTXs) are cytotoxins produced by some marine cyanobacteria. Their unique structures show a great potency as an anticancer agent. The limited availability of OTX derivatives in nature provides little information about their biological activity. Some of OTX activities have been tested in the in vitro or in vivo studies toward cancer cell lines, but their exact mechanism of action on the target is unclear. In this study, we used the network pharmacology analysis method to predict the target and mechanism of action of oscillatoxin D (OTX-D), 30 methyl oscillatoxin D (30-methyl-OTX-D), oscillatoxin E (OTX-E), and oscillatoxin F (OTX-F). There are 20 possible targets of the four compounds toward cancer, and the main targets of them are PIK3CA, CDK1, and MTOR. This was also followed by the molecular docking study to understand the interaction between the four compounds and their targets. Molecular docking showed that the four compounds interacted well with the key targets. In this study, four derivatives of OTXs and their three key targets for the anticancer action were revealed suggesting multiple signaling pathways, including PD-L1 expression and PD‑1 checkpoint pathway in cancer, proteoglycans in cancer, and pathways in cancer, establishing a theoretical framework for the further experimental study.Осциллатоксины (OTXs) —  это цитотоксины, продуцируемые некоторыми морскими цианобактериями. Их уникальные структуры показывают высокую эффективность в качестве противораковых средств. Ограниченная доступность производных OTXs в природе дает мало информации об их биологической активности. Было тестировано несколько активностей OTXs в исследованиях in vitro или in vivo в отношении линий раковых клеток, но их точный механизм действия на мишень не ясен. В данном исследовании мы использовали метод сетевой фармакологии для прогнозирования мишеней и механизмов действия осциллатоксина D (OTX-D), 30 метил-осциллатоксина D (30-метил-OTX-D), осциллатоксина E (OTX-E), и осциллатоксина F (OTX-F). Существуют 20 возможных мишеней четырех соединений против рака и их основными мишенями являются PIK3CA, CDK1 и MTOR. Затем было проведено исследование методом молекулярного докинга для понимания взаимодействия между 4 соединениями и их мишенями. Молекулярный докинг показал, что 4 соединения хорошо взаимодействовали с ключевыми мишенями. В данной работе было выявлено 4 производных OTXs и 3 ключевых мишени для противоракового действия, указывая на множественные сигнальные пути, включая путь экспрессии PD-L1 и контрольной точки PD-1 при раке, протеогликаны при раке и пути при раке, устанавливая теоретические рамки для дальнейшего экспериментального исследования

Solvation thermodynamics of organic molecules by the molecular integral equation theory : approaching chemical accuracy

The integral equation theory (IET) of molecular liquids has been an active area of academic research in theoretical and computational physical chemistry for over 40 years because it provides a consistent theoretical framework to describe the structural and thermodynamic properties of liquid-phase solutions. The theory can describe pure and mixed solvent systems (including anisotropic and nonequilibrium systems) and has already been used for theoretical studies of a vast range of problems in chemical physics / physical chemistry, molecular biology, colloids, soft matter, and electrochemistry. A consider- able advantage of IET is that it can be used to study speci fi c solute − solvent interactions, unlike continuum solvent models, but yet it requires considerably less computational expense than explicit solvent simulations

A computational study on the role of solvents and conformational fluctuation of macromolecules towards drug design

A Thesis Submitted in Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Life Sciences of the Nelson Mandela African Institution of Science and TechnologyHeat shock protein 90 (Hsp90) represents an important chemotherapeutic target in the treatment of various ailments including cancer and neurodegenerative diseases. The protein is responsible for controlling and regulating the growth of nearly 200 client proteins known to overexpress in tumour or cancer cells. Targeting Hsp90 and inhibiting its chaperone machinery function results in proteasome degradation of the client protein and hence treatment of the disease. In this thesis, different computational docking protocols, the role of water and conformational fluctuations in drug design for the discovery and identification of new Hsp90 inhibitors are reported. In particular, the sensitivity of different docking protocols to crystal structure with and without water, relaxed complex scheme (RCS) or ensemble-based structures holo and apo structures with and without water, the effects of including a different amount of water in the protein active site on the thermodynamics of ligand binding to protein structures are reported. There is sensitivity of results to different docking protocols, RCS lowers the binding energy in comparison to crystal structure, holo ensemble with strong ligand bound improves the docking results. Since biological activities of small molecules highly depends on the conformation, molecular structure, charge distribution and non-trivial response to solvents. The thesis further explored the role of different solvents viz polar protic, polar aprotic, and non-polar on the conformation of curcumin as a model drug/natural product. Well-tempered metadynamics (WT-MetaD), an enhanced sampling method employing OPLS-AA force field in an isobaricisothermal (NPT) ensemble was used to investigate the related solvent effects. The orientation and conformational of curcumin was solvent dependent, the free energy for curcumin in solvents and vacuum portrayed a different behaviour. Curcumin exists in different configuration and conformations in different solvents. The trans-conformation was more stable in polar aprotic solvents capable of solubilizing curcumin whereas the cis-conformation was more stable in polar protic solvents i.e water where it has marginal solubility. Finally, the thesis reports on the influence of solvents on kinetics and residence time of drug unbinding in host-guest complexes. The effect of polar aprotic and polar protic solvents on kinetics and residence time of drug unbinding from a nanoparticle was investigated using chitosan-toussantine-A as a model system. WT-MetaD was used to study the kinetics and residence time. Results show that the kinetics and residence time of drug unbinding was affected by solvents. Slow unbinding kinetics of k off = 0.045 ms 1 was observed for the system formulated with water, a polar protic solvent, while fast unbinding kinetics with k off = 1000 ms 1 was observed in system formulated with DMSO solvent. Furthermore, the interaction of chitosan-toussantine-A complex in water was observed to be stable than in DMSO. The approaches used in this thesis pave the ways and can further be extended to investigate more problems in drug design ranging from protein-ligand interaction, solution conformation of small molecules and host-guest kinetics. Since the new reported small molecules as Hsp90 inhibitors are approved for other indication, the inhibitors are recommended for further pre-clinical and clinical testing as new Hsp90 inhibitors for cancer treatment