GERMANTOWN, MD, United States
GERMANTOWN, MD, United States

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Arora P.,Iowa State University | Slipchenko L.V.,Purdue University | Webb S.P.,Verachem, Llc | Defusco A.,Iowa State University | Gordon M.S.,Iowa State University
Journal of Physical Chemistry A | Year: 2010

The simplest variational method for treating electronic excited states, configuration interaction with single excitations (CIS), has been interfaced with the effective fragment potential (EFP) method to provide an effective and computationally efficient approach for studying the qualitative effects of solvents on the electronic spectra of molecules. Three different approaches for interfacing a non-self-consistent field (SCF) excited-state quantum mechanics (QM) method and the EFP method are discussed. The most sophisticated and complex approach (termed fully self consistent) calculates the excited-state electron density with fully self-consistent accounting for the polarization (induction) energy of effective fragments. The simplest approach (method 1) includes a strategy that indirectly adds the EFP perturbation to the CIS wave function and energy via modified Hartree-Fock molecular orbitals, so that there is no direct EFP interaction with the excited-state density. An intermediate approach (method 2) accomplishes the latter in a noniterative perturbative manner. Theoretical descriptions of the three approaches are presented, and test results of solvent-induced shifts using methods 1 and 2 are compared with fully ab initio values. These comparisons illustrate that, at least for the test cases examined here, modification of the ground-state Hartree-Fock orbitals is the largest and most important factor in the calculated solvent-induced shifts. Method 1 is then employed to study the aqueous solvation of coumarin 151 and compared with experimental measurements. © 2010 American Chemical Society.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.48M | Year: 2015

DESCRIPTION provided by applicant Host molecules such as cyclodextrins and cucurbiturils can andapos captureandapos smaller molecules and affect their physical and chemical behavior The stronger the host molecule holds onto i e binds its smaller andapos guestandapos the larger the effect ca be Host molecules themselves can also be chemically altered i e derivatized which can change how strongly they bind guest molecules as well as their own physical properties Scientists are discovering many human health related applications for host guest technology including improvement of the properties of drugs to make them more effective and safer potential scavengers for chemical warfare agent removal and clean up of environmental chemical pollutants The amount of basic research as well as applied industrial Randamp D in this area is expanding rapidly Given a particular andapos guestandapos molecule e g drug candidate chemical pollutant key pieces of information Randamp D scientists require is the host guest binding affinity and the association dissociation rates This SBIR project aims to develop a software tool that can accurately predict these host guest binding properties e g binding free energy This would allow Randamp D scientists to carry out computational experiments reducing the number of expensive and time consuming bench experiments required There is a current need for such a software tool to be developed because as recently demonstrated by a blinded test challenge existing tools are not accurate enough to provide useful information to researchers Very recent studies indicate that the accuracy of the predictions can be significantly improved by combining quantum mechanical QM energy functions with rigorous statistical mechanics However these proof of concept studies have yet to be translated into a robust computational tool suitable for applied Randamp D Therefore this project will interface VeraChemandapos s current statistical mechanics software package VM with the widely used quantum chemistry package GAMESS and implement drivers for various computational schemes to achieve this goal In this proposed hybrid methodology a Boltzmann distribution of molecular conformations will still be generated via a thorough conformational search as it is for classical VM however the conformational search will not solely rely on molecular mechanics but will be guided by the more reliable QM potential QM potentials will also be used for entropy terms including a treatment of anharmonic effects Full advantage will be taken of recent dramatic improvements in reliability of semi empirical QM SEQM with optional corrections at higher levels of QM Turnaround of calculations will be speeded up by parallel processing and a sophisticated conformer filter vetting process PUBLIC HEALTH RELEVANCE There are cage like molecules scientists call andapos hostsandapos which can capture smaller andapos guestandapos molecules and by holding onto them can alter their behavior in a way beneficial to human health The guest molecule could be a pharmaceutical drug environmental chemical pollutant or even a chemical warfare agent This project aims to develop a software tool that can predict how strongly a particular host molecule will hold onto a particular guest molecule thereby helping scientists design host molecules for use in human health related products and services


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 147.88K | Year: 2014

Project Summary Host molecules, such as cyclodextrins and cucurbiturils, can 'capture' smaller molecules and affect their physical and chemical behavior. The stronger the host molecule holds onto, i.e. binds, its smaller 'guest' the larger the effect can be. Host molecules themselves can also be chemically altered (i.e. derivatized), which can change how strongly they bind guest molecules, as well as their own physical properties. Scientists are discovering many human health-related applications for host-guest technology, including improvement of the properties of drugs to make them more effective and safer, potential scavengers for chemical warfare agent removal, and clean-up of environmental chemical pollutants. The amount of basic research as well as applied/industrial RandD in this area is expanding rapidly. Given a particular 'guest' molecule (e.g. drug candidate, chemical pollutant) key pieces of information RandD scientists require is the host-guest binding affinity and the association/dissociation rates.


Chen W.,Verachem, Llc | Gilson M.K.,Verachem, Llc | Webb S.P.,Verachem, Llc | Potter M.J.,Verachem, Llc
Journal of Chemical Theory and Computation | Year: 2010

We present the first application of the mining minima algorithm to protein-small molecule binding. This end-point approach uses an empirical force field and implicit solvent models, treats the protein binding site as fully flexible, and estimates free energies as sums over local energy wells. The calculations are found to yield encouraging agreement with experimental results for three sets of HIV-1 protease inhibitors and a set of phosphodiesterase 10a inhibitors. The contributions of various aspects of the model to its accuracy are examined, and the Poisson-Boltzmann correction is found to be the most critical. Interestingly, the computed changes in configurational entropy upon binding fall roughly along the same entropy-energy correlation previously observed for smaller host-guest systems. Strengths and weaknesses of the method are discussed, as are the prospects for enhancing accuracy and speed. © 2010 American Chemical Society.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.17M | Year: 2011

DESCRIPTION (provided by applicant): Many drugs are small molecules that act by binding to a specific protein and thus blocking or altering its actions. For example, the HIV protease inhibitors are important AIDS treatments that work by binding in the active site of the protease enzyme and preventing it from helping to make new viruses. When scientists identify a protein, like HIV protease, as being important in a disease process, a next step often is to determine its three-dimensional structure in great detail. This structure then provides valuable guidance to chemists trying to design a small molecule that will bind the protein tightly. However, even when they know the structure of the protein, there is still a lot of trial and error in designing a drug. Many researchers have worked on computer programs to help predict whether a given molecule will bind a given protein, but without much success. Now, new software that VeraChem has been developing over the last few years is giving very good results for thisproblem. However, the software takes a long time to run and would be far more useful if it were much faster. For example, if chemists had an idea for a new compound to try, they could get the answer in a minutes instead of a few days. They could use the method to quickly and cheaply test thousands of compounds in chemical catalogs. And they could check whether a compound that works against their protein would keep working against mutant forms of the protein and thereby avoid drug-resistance. Thus, a fast version of VM2 would be very useful and would be a valuable commercial product. Speeding up VeraChem's method, VM2, is not as simple as running it on a faster computer, because individual computers have not been getting much faster in recent years. What is changing, though, is that computers are being made with more and more processors. The goal of this project is to speed up VM2 enormously by spreading its computational work across large numbers of separate processors in a single computer, in a cluster of computers, and even in a video card. This is not a simple task, but researchers have been able to speed up related molecular calculations in this way, and we are confident the same can be done for VM2. PUBLIC HEALTH RELEVANCE: We want to let scientists design new medicines more quickly with a computer program. The problem is that the program takes too long to do its calculations. This project is to speed up the calculations by changing the program so that it can make a large number of computer processors to work together to calculate the answers in a short time.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 140.80K | Year: 2010

DESCRIPTION (provided by applicant): Many drugs are small molecules that act by binding to a specific protein and thus blocking or altering its actions. For example, the HIV protease inhibitors are important AIDS treatments that work by binding in the active site of the protease enzyme and preventing it from helping to make new viruses. When scientists identify a protein, like HIV protease, as being important in a disease process, a next step often is to determine its three-dimensional structure in great detail. This structure then provides valuable guidance to chemists trying to design a small molecule that will bind the protein tightly. However, even when they know the structure of the protein, there is still a lot of trial and error in designing a drug. Many researchers have worked on computer programs to help predict whether a given molecule will bind a given protein, but without much success. Now, new software that VeraChem has been developing over the last few years is giving very good results for this problem. However, the software takes a long time to run and would be far more useful if it were much faster. For example, if chemists had an idea for a new compound to try, they could get the answer in a minutes instead of a few days. They could use the method to quickly and cheaply test thousands of compounds in chemical catalogs. And they could check whether a compound that works against their protein would keep working against mutant forms of the protein and thereby avoid drug-resistance. Thus, a fast version of VM2 would be very useful and would be a valuable commercial product. Speeding up VeraChem's method, VM2, is not as simple as running it on a faster computer, because individual computers have not been getting much faster in recent years. What is changing, though, is that computers are being made with more and more processors. The goal of this project is to speed up VM2 enormously by spreading its computational work across large numbers of separate processors in a single computer, in a cluster of computers, and even in a video card. This is not a simple task, but researchers have been able to speed up related molecular calculations in this way, and we are confident the same can be done for VM2. PUBLIC HEALTH RELEVANCE: We want to let scientists design new medicines more quickly with a computer program. The problem is that the program takes too long to do its calculations. This project is to speed up the calculations by changing the program so that it can make a large number of computer processors to work together to calculate the answers in a short time.


PubMed | Verachem, Llc
Type: Journal Article | Journal: Journal of chemical theory and computation | Year: 2012

We present the first application of the mining minima algorithm to protein-small molecule binding. This end-point approach use an empirical force field and implicit solvent models, treats the protein binding-site as fully flexible and estimates free energies as sums over local energy wells. The calculations are found to yield encouraging agreement with experiment for three sets of HIV-1protease inhibitors and a set of phosphodiesterase 10a inhibitors. The contributions of various aspects of the model to its accuracy are examined, and the Poisson-Boltzmann correction is found to be the most critical. Interestingly, the computed changes in configurational entropy upon binding fall roughly along the same entropy-energy correlation previously observed for smaller host-guest systems. Strengths and weaknesses of the method are discussed, as are the prospects for enhancing accuracy and speed.


Verachem, Llc | Entity website

VDisplay VDisplayis a freely available 3D molecular viewer which reads the SDfiles produced by Vcharge and Vconf and provides an easy, graphical way to view the results on a Windows computer. Vdisplay can also read and display SDfiles produced by other programs ...


Verachem, Llc | Entity website

Profile VeraChem LLCwas founded in 2000 to advance the state of the art in computer-aided drug-discovery and molecular design by developing computational chemistry methods that are based on cutting edge basic science, but are also applicable in applied science research settings. Efficient high performance software implementations of these methods coupled with comprehensive user support are a central company strategy for product development ...


Verachem, Llc | Entity website

VCharge VChargeprovides fast, easy access to accurate partial charges for virtually any drug-like compound. It is thus valuable in a wide range of modeling and QSAR applications ...

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