Relationship between Mechanics and Drug Binding - Report Example

The relationship between quantum mechanics and drug binding Relationship between Mechanics and Drug Binding IntroductionThe type of mechanics which has found wide application in drug binding is Quantum Mechanics (QM). The use of mechanics techniques in computational drug design is becoming popular day-by-day. This is mainly because high accuracy is needed to estimate drug binding affinities. For low to medium throughput in silico screening, efficient estimations have been advanced in the recent past such as linear scaling Quantum Mechanics in which the computation-time scales are almost linear with the number of basic functions. Moreover, Quantum Mechanics- based approaches have been applied recently in the evaluating energies, optimizing molecular structures and determination of protonation states of ionizable elements. For a high-throughput in silico screenings, quantum mechanics-based procedures have been used to derive quantitative structure-activity relationship models. It is projected that the use of quantum mechanics continue growing in all the stages of Computer Assisted drug design. Though, wide sampling of the conformational treatment of solution and space of macro-molecules are still the limiting factors for the wide use of Quantum mechanics in drug binding. Accurate models for calculating the binding free energy between proteins and small molecules are required for drug design and development. The growing popularity of QM techniques in Computer- Assisted drug design is not only a consequence of increasing computing power, but it is also because of the first principle nature of the quantum mechanics. For instance, quantum mechanics calculations were carried out to examine differences in binding affinities after modification of upon modification of –CH2 − linkers into carbonyls. The routine application of quantum mechanics in all phases of in drug binding is the rational step in drug design. The very first principles of quantum mechanics allow it to systematically improve the accuracy of the descriptions of the characteristics of drug molecules interactions. The design and development of new drugs is a complex and expensive enterprise, which requires the inter-play of several scientific facets through integrated multi-disciplinary teams. The key roles of the computational chemistry within this multi-disciplinary team have become firmly established. Metric points to the measurable effect of computer-aided medicine design across a discovery timeline. More recently, computational drug chemists have a wide range of chemical databases, informatics and silicon tools at their disposal. The available design tools include pipelining tools, advanced molecular graphics, sub-structure searching tools, which are used for deriving quantitative structure- activity relationships, statistical packages, pharmacophore-based analysis, and receptor-ligand binding tools. In the recent analyses of the computational tools, major pharmaceutical companies, among the lowest ranked techniques was the use of quantum mechanics (QM), alongside the molecular dynamics (MD). This is very interesting to note given that the use quantum mechanics had featured amongst the first techniques in the field of computer-aided drug binding. Quantum mechanics has been used in the calculation of polarity descriptors, which are used in quantitative structure-activity relationships, commonly referred to as QSAR. These polarity descriptors included the partially charged elements derived from the wave-function of the energies and molecules of its lowest unoccupied and highest occupied molecular orbitals. This practice has continued to date with more advanced application of Quantum mechanics. The concepts Quantum mechanics has also been applied by medicinal chemists to understand and theoretically mitigate the energetic strains in drugs, resulting from their bindings to receptor. This played a crucial role in the development of dorzolamide in the early years of 1990s, The major compound used during the development of development of dorzolamide had (S) - and (R)- enantiomers. The crystallographic structures of these two elements explained the greater strength of the (S) in terms of internal isobutyl side-chain and N-S-C-S moiety conformations. These were supported by the use of Quantum Mechanics calculations. The Quantum Mechanics approaches in drug binding play key roles in guiding selection of compounds for use in medicinal chemist in order synthesize and assay. In the olden days of quantum mechanics, Dirac, Schrodinger, and other scientists had argued made several research works on how quantum can be applied in drug binding. Several experiments had been carried out in a bid to examine the relationship between quantum mechanics and drug binding. These experiments included Löwdin, Pauling, and Pullmans. Quantum Mechanics-based approaches have been used for prediction of internal energetics associated with drug binding. In the recent past, there have been rapid changes in quantum chemical application software programs and computational power, enabling the use of Quantum Mechanics concepts to more complex and larger systems. It true, however, that the most sophisticated quantum mechanics can only be used to reasonably modest atom sizes, normally 10s of atoms. Application of Quantum Mechanics in calculating optimize structures and energies Quantum mechanics is the most preferred method for electronic structures and energies calculations. Quantum mechanics techniques are also used in examining potential energy hyper-surface of tiny molecules. More recently, quantum mechanics-based techniques have been used to examine both the solvation effects and internal energies of the ligand structure. The analysis shows that two- thirds of the bio-active conformations of tiny-molecule inhibitors lie within about 0.5k cal /mol of a local minimum. And conformation with penalties above 2 kcal /mol is attributable to the structure determination inaccuracies. However, quantum mechanics can only be applied to molecular structures of limited sizes so that quantum mechanics has to be simplified so as to cope with the available computational powers. Quantum Mechanics and Molecular Mechanics The calculation procedures based on quantum mechanics and molecular mechanics combine the strengths of both efficiency (molecular mechanics) and accuracy (quantum mechanics). They are majorly employed to models of chemical reactions and electronic processes in bio-molecular structures. Quantum mechanics and molecular mechanics can be applied in preparing the chemical structures of proteins and small molecules. These include optimizing the binding postures obtained from docking process and refining the geometrical alignment of enzymes active sites acquired from a harmonically controlled minimization with or X-ray structures or molecular structures. It has been proposed that in the process of drug discovery molecular quantum mechanics or molecular mechanics is important in examining the effects of the various substituents on the mode of drug structural binding. Molecular mechanics/Quantum is also useful in describing the charges polarization process and electron transfer, which may not be possible by ordinary methods. Summary There is a close link between drug binding and mechanics. For instance, several quantum mechanics-based techniques already play crucial roles in many stages of Computer-Assisted Drug Design and development. It is projected that the use of mechanics will continue to have great impacts in this field due to the increasing computing power and developments of more efficient computer algorithms. The compromise between efficiency and accuracy is a continuous issue in the use of the techniques of mechanics. It is of importance to carefully choose the most appropriate method for drug design and development. Techniques of quantum mechanics techniques should be chosen only in cases where there are real advantages over the classical techniques. The first stage of Computer-Assisted Drug Design, e.g., a high-through-put docking process, which is used in identifying compounds. It requires full sampling of small molecule conformations within the proteins binding sites. Such elaborate sampling requires an approximated energy-functions and projected properties thereof. The energies are normally calculated by ordinary methods. In the succeeding phase, hits should be optimized to form leads, which don not need extensive sampling but a high degree of accuracy due to the small variations in the binding energies. Therefore, quantum mechanics should be used on the hits to shed more light on the binding energies. The techniques of quantum mechanics are, particularly, important to examine the polarization effects and charge transfers, which are normally noticeable in systems containing charged elements. Importantly, the first thing before starting the process of Computer- Assisted Drug Design, it is necessary to examine the project status. References Nag, A., & Dey, B. (2011). Computer-aided drug design and delivery systems. New York: McGraw-Hill. Paneth, P., & Dybala-Defratyka, A. (2010). Kinetics and dynamics. Dordrecht: Springer. Ramachandran, K., Deepa, G., & Namboori, K. (2008). Computational chemistry and molecular modeling. Berlin: Springer. Reynolds, C., Holloway, M., & Cox, H. (1995). Computer-aided molecular design. Washington, DC: American Chemical Society. Read More