Current and emerging opportunities for molecular simulations in structure-based drug design

An overview of the current capabilities and limitations of molecular simulation of biomolecular complexes in the context of computer-aided drug design is provided. Steady improvements in computer hardware coupled with more refined representations of energetics are leading to a new appreciation of the driving forces of molecular recognition. Molecular simulations are poised to more frequently guide the interpretation of biophysical measurements of biomolecular complexes. Ligand design strategies emerge from detailed analyses of computed structural ensembles. The feasibility of routine applications to ligand optimization problems hinges upon successful extensive large scale validation studies and the development of protocols to intelligently automate computations

Femtosecond-assisted intrastromal corneal ring implantation for keratoconus treatment: a comparison with crosslinking combination

Purpose: To compare visual outcomes, corneal astigmatism, and keratometric readings in patients with keratoconus who underwent intrastromal corneal ring implantation (ICRSI) alone with those who underwent ICRSI combined with ultraviolet A riboflavin-mediated corneal collagen crosslinking (CXL). Methods: Pre- and post-operative best-corrected distance visual acuity (BCDVA), spherical error, cylindrical error, and mean keratometry were retrospectively compared over a period of 2 years in patients with keratoconus who underwent only ICRSI (group 1) versus those in patients who underwent combined ICRSI-CXL (group 2). Results: Thirty-two eyes of 31 patients were evaluated. CXL was performed in 10 cases (31%), and there were no complications or need for ring repositioning. BCDVA improved from 0.54 to 0.18 in the group 1 and from 0.56 to 0.17 in the group 2. Spherical and cylindrical errors and mean keratometry values significantly decreased in both groups. No patient postoperatively had visual acuity (VA) of less than 20/60 on refraction, and 78% exhibited VA better than or equal to 20/40 with spectacles (72% of group 1 and 90% of group 2). Improvement in the spherical equivalent (SE) value was observed in the group 1 (from -5.89 &#177; 3.37 preoperatively to -2.65 &#177; 2.65 postoperatively; p<0.05) and group 2 (from -6.91 &#177; 1.93 preoperatively to -2.11 &#177; 3.01 postoperatively; p<0.05). Conclusion: Both techniques can be considered safe and effective in improving VA and refractive SE values, in decreasing the curvature of the cone apex in the topographical analysis, and in decreasing corrected diopters postoperatively in patients with keratoconus

Classical polarization in hybrid QM/MM methods

We have presented a method for modeling polarization in hybrid QM/MM calculations. The method, which expresses the induced dipoles as a set of "induced" charges, is based on the induced dipole approach and methodology for calculating potential-derived point charges from distributed multipole series. The method has the advantage that the same methodology can be used to determine the induced charges and the potential derived charges and so both sets of charges are rigorously defined within the same framework. This underlying link with the wave function makes the method particularly suitable for use in hybrid QM/MM calculations. Here we assess the importance of explicit polarization in the classical part of a QM/ MM system with regard to improving the classical description and the consequent effects on the quantum description. The main advantages of the induced charge approach are that the method is readily interfaced with quantum mechanical methods and that induced charges are more readily interpreted than induced dipoles. The ease of interpretation is illustrated by analysis of the charges involved in dimeric and trimeric hydrogen bonded systems. The method for treating the MM polarization has been validated by a regression analysis of the charges induced in both the QM and MM systems against those derived from full quantum mechanical calculations. The method has also been validated using two energy decomposition approaches, which show that MM polarization makes a significant and reliable contribution to the QM - MM interaction energy in a hybrid system. The distance dependency of the induced charges is investigated in calculations on methylsuccinyl-Ala-Ala-Pro-Ala chlormethyl ketone interacting with human neutrophil elastase and propranolol interacting with asparagine residues in a model of the beta(2)-adrenergic receptor