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200804.08.08 New ICM Paper: New method for the assessment of all drug-like pockets across a structural genome. Nicola G, Smith CA, Abagyan R. New method for the assessment of all drug-like pockets across a structural genome. Comput Biol. 2008 Apr; 15(3):231-40. Department of Molecular Biology, The Scripps Research Institute, La Jolla, California. Abstract: With the increasing wealth of structural information available for human pathogens, it is now becoming possible to leverage that information to aid in rational selection of targets for inhibitor discovery. We present a methodology for assessing the drugability of all small-molecule binding pockets in a pathogen. Our approach incorporates accurate pocket identification, sequence conservation with a similar organism, sequence conservation with the host, and structure resolution. This novel method is applied to 21 structures from the malarial parasite Plasmodium falciparum. Based on our survey of the structural genome, we selected enoyl-acyl carrier protein reductase (ENR) as a promising candidate for virtual screening based inhibitor discovery.
03.20.08 New ICM Publication: A new method for ligand docking to flexible receptors New ICM publication by the Scripps Research Institute and MolSoft scientists. See: Bottegoni G, Kufareva I, Totrov M, Abagyan R. A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE). J Comput Aided Mol Des. 2008 Feb 14; Paper link: Abstract Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor, or on the prior knowledge of multiple conformations representing the variation of the pocket, or on a known bounding box for the ligand. Here we described a general induced fit docking protocol that requires only one initial pocket conformation and identifies most of the correct ligand positions as the lowest score. We expanded a previously used diverse "cross-docking" benchmark to thirty ligand-protein pairs extracted from different crystal structures. The algorithm systematically scans pairs of neighbouring side chains, replaces them by alanines, and docks the ligand to each 'gapped' version of the pocket. All docked positions are scored, refined with original side chains and flexible backbone and re-scored. In the optimal version of the protocol pairs of residues were replaced by alanines and only one best scoring conformation was selected from each 'gapped' pocket for refinement. The optimal SCARE (SCan Alanines and REfine) protocol identifies a near native conformation (under 2 A RMSD) as the lowest rank for 80% of pairs if the docking bounding box is defined by the predicted pocket envelope, and for as many as 90% of the pairs if the bounding box is derived from the known answer with approximately 5 A margin as used in most previous publications. The presented fully automated algorithm takes about 2 h per pose of a single processor time, requires only one pocket structure and no prior knowledge about the binding site location. Furthermore, the results for conformationally conserved pockets do not deteriorate due to substantial increase of the pocket variability.
03.11.08 Free Online Tutorial Dates Released for May through to July. Click here for information on the upcoming online demonstrations.
03.03.08 New Review Article from MolSoft on Flexible Docking
Here is a link to a new publication in Current Opinion Structural
Biology on flexible docking by Dr. Totrov (MolSoft) and Prof. Abagyan (Scripps). The paper highlights all the recent development for including multiple receptor conformations in docking to represent ligand induced fit.
02.14.08 New Tutorial: How to model the effect of a mutation on protein structure. Click here for a new tutorial on how to make a mutation in a protein structure and optimize. 02.14.08 MolSoft Scientists Collaborate with Schering Plough to Identify New GPCR Inhibitors using ICM. Click here to read how MolSoft and Schering Plough scientists identified new inhibtitors for a GPCR using MolSoft's drug discovery products. The structure-based development of MCH-R1 and other GPCR antagonists is hampered by the lack of an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands is used explicitly to shape and optimize the binding site) followed by docking-based virtual screening. Top scoring compounds identified virtually were tested experimentally in an MCH-R1 competitive binding assay, and six novel chemotypes as low micromolar affinity antagonist "hits" were identified. This success rate is more than a 10-fold improvement over random high-throughput screening, which supports our ligand-steered method. Clearly, the ligand-steered homology modeling method reduces the uncertainty of structure modeling for difficult targets like GPCRs.
02.04.08 New Tutorial: How to dock to multiple receptor conformations. There is a new tutorial online here The tutorial uses Aldose Reductase as an example. Aldose Reductase has a flexible loop in the ligand binding pocket vicinity which enables a variety of inhibitors to bind and therefore in order to identify these ligands via docking it is necessary to sample the conformations of this loop and dock to an ensemble of structures.
200712.15.07 New Docking tutorials - Docking to Electron Density and Focused Markush Library Docking How to dock a ligand to an electron density map. The ICM X-Ray AutoFit is an automated method to fit a ligand into electron density. The tool combines the powerful ICM docking algorithm with an electron density fitting function. Click here for step by step instructions. How to dock a focused Markush library. A Markush library can be generated on the fly and docked using ICM. In this example we use the roscovitine ligand bound to CDK5 to identify scaffolds which may improve ligand-receptor interaction. 10.23.08 New Slide Transition EffectIn ICM version 3.5-1l a new blending transition effect between slides is available. To see this in action download the latest version of ICM or the free ICM-Browser and view this icb file: http://www.molsoft.com/~andy/blend.icb To generate this transition effect:
October 22nd 2007
As a quarter of million people fled their homes amid fierce wildfires that had burned 100,000 acres around San Diego County, Molsoft opened its doors for the families of the escapees. Children, pets, and adults have found a comfortable home at Molsoft and were given a place to stay, sleep, access internet and play video games. Games, food, laughter and partial property destruction made their stay at Molsoft more comfortable. The training class became an information center from which the families were following the fate of their homes. October 17th 2007 MolSoft launches the ICM Forum. Please sign up and contribute with questions/answers and interact with other ICM users worldwide. October 12th 2007 MolSoft announces a series of online demonstrations as a new way of teaching the ICM suite of software. Click here for more information. July 12th 2007
Molecular Movie Making Made Easy June 2nd 2007
MolCart Compound Database Update May 25th 2007 The latest version 3.5 for all ICM products has been released for Windows, Mac , Linux and SGI.Please download the latest version of ICM from our support center. Some of the new features include:
For more details please see the Release Notes.
March 27th 2007 Maxim Totrov PhD to present data at American Chemical Society National Meeting On March 27th 2007 Dr. Maxim Totrov (Principal Scientist - MolSoft LLC) will be giving a presentation entitled "Chemical superposition and pharmacophore elucidation by SCAPFOld: Self-consistent atomic property field optimization" at the American Chemical Society 233rd National Meeting & Exposition, Chicago, IL USA. The presentation abstract can be found here. March 22nd to 23rd 2007 ICM Workshop Once again the ICM Workshop sold out quickly and we had a full class of students eager to learn about Protein Structure and Drug Discovery using MolSoft's ICM software. The first day and a half of training was presented by Prof. Ruben Abagyan (Scripps Research Institute). Prof. Abagyan gave lectures and demonstrations on ICM sequence and structure analysis, molecular modeling and cheminformatics. Friday afternoon was devoted to small molecule docking, virtual ligand screening and protein-protein docking led by Dr. Maxim Totrov (Principal Scientist - MolSoft). The participants ran docking examples such as virtual screening of small ligand databases to identify known inhibitors of the cyclooxygenase receptor and protein-protein docking of subtilisin and chymotrypsin. All the participants agreed that the workshop will help them greatly when they return to the lab and would highly recommend the training to their colleagues. If you were unable to attend this workshop we are holding workshops in May and September this year. Please click here for more details and sign up early to guarantee your place. 2006 August 1st 2006 MolSoft Awarded NIH SBIR Phase I Grant to develop protein surface annotation software MolSoft was recently awarded a NIH SBIR Phase I Grant to develop an integrated protein surface annotation suite of software for biologists and chemists. The software will allow users to apply several binding site prediction methods and analyze the results. These new algorithms include a protein-protein interface prediction method for small molecule binding sites and a surface structural motif detection and visualization method. July 1st 2006 MolSoft Receives Bill and Melinda Gates Foundation AIDS Research Grant Scientists at MolSoft LLC will be working as part of a multidisciplinary team led by Susan Zolla-Pazner Ph.D. (New York University School of Medicine) on a grant funded by the Bill and Melinda Gates Foundation entitled "The V3 Loop: A Conserved Structure of gp120 that Can Induce Broadly Neutralizing Antibodies Against HIV-1" MolSoft LLC is excited to be leading the structure-based engineering of the V3-carrier immunogen. Using our experience with similar efforts we will undertake ab initio loop modeling of protein segments consisting of the central portions of the V3 signature sequences and modeling of carrier joining sequences. For more information please see the press release in the New York Times. July 1st 2006 MolSoft and Virginia Tech collaborate to work on malaria vector control MolSoft and Virginia Tech will be working together on a 3-year project funded by the Foundation of the National Institutes of Healt to apply state-of-the-art computer modeling and chemical synthetic approaches to produce highly potent and selective anticholinesterases (AChEs) for malaria vector control. MolSoft's ICM software will be used to build homology models of AChEs and virtual screening will be applied to identify selective inhibitors. ICM-Chemistry will then be applied to optimize the lead compounds. February 8th 2006: From Physics to Biology: the interface between experiment and computation BIFI 2006 - II International Conference, Zaragoza Spain. Claudio Cavasotto PhD (Senior Scientist - Molsoft) has been invited to present a talk entitled "Ligand docking and virtual screening in structure-based drug discovery" at the BIFI 2006 - II International Conference, Zaragoza, Spain. His talk will be on February 8th 2006 and more details about the conference can be found here. January 25th-27th 2006 Three-Day ICM Workshop.
January 1st 2006 MolSoft and the Mayo Clinic College of Medicine Collaboration Scientist at the Mayo Clinic and MolSoft will be collaborating on a project to model G-protein coupled receptors (GPCRs) which are key receptors for a large number of disease pathways. The aim is to use MolSoft's proprietary software to build highly-refined and rigorously validated models of GPCRs and to use these models to guide experimental work at the Mayo Clinic.
2005 September 29th-30th 2005 Successful Workshop On September 29th-30th an international group of ICM users from academia and industry gathered for our ICM Workshop entitled "Protein Structure and Drug Discovery" Click here to see what went on. August 3rd, 2005 New Version Release Molsoft has released the latest version (3.4) of ICM. This version includes a number of new features as described in the Release Notes. The most significant addition is the incorporation of ICM Molecular Documents and Presentation (Patent Pending). These can be constructed and viewed in ICM, they can consist of text linked to molecular animations and transitions. The animations and transitions are fully-interactive and can be interrupted without any loss of information. For more information on ICM Molecular Documents and Presenations please click here.
April 14th, 2005 New Product Release.
April 25th, 2005 New SGI version release.
April 5th, 2005 2004
August 10th, 2004
July 15th, 2004 July 30, 2004 California State University at Fullerton Expands Use of ICM-Pro to New Computational Biology Curriculum Being Offered in 2005-06 Molsoft is pleased to learn that the Department of Chemistry and Biochemistry at California State University, Fullerton, is expanding its teaching use of ICM-Pro. CSU Fullerton began using ICM-Pro for training undergraduate chemistry and biochemistry students in Spring 2004. ICM-Pro has also been used to teach structural bioinformatics to students seeking a Certificate in Bioinformatics through CSUFs Extended Education program. Beginning in 2005-06, ICM-Pro will be featured in a new computational biology program for chemistry and biochemistry majors [more]. July 20-21st Molsoft Conducts ICM Workshop in New Jersey USA On the 20-21st of July 2004 sixteen people attended the ICM workshop entitled "In Silico Drug Discovery". The workshop was held at Bristol Myers Squibb at Princeton New Jersey.
June 25th, 2004 Molsoft LLC is pleased to announce a collaboration with the Burnham Institute, La Jolla, on a STTR NIH funded grant entitled "15 - Deoxy -12,14-prostaglandin J2 as a ligand of RXRalpha".
March 17, 2004 Molsoft LLC Receives Phase I STTR to Develop Beta-Catenin Antagonists Molsoft LLC received a Phase I STTR award from the National Institutes of Health, National Cancer Institute, for the project entitled. Rational Development of TCF/Beta-Catenin Antagonists. The project will combine Molsoft's novel in silico lead development platform with the cancer biology resources at The Burnham Institute to discover and characterize small molecule ligands using the beta-catenin structure both alone and in complex with TCF. Beta-catenin signaling has been implicated in a number of malignancies, which makes the beta-catenin/TCF interaction an promising target for the prevention and treatment of a variety of tumors and leukemia, and the project proposes to develop a novel generation of drugs active against various forms of cancer.
2003 July 25, 2003 Molsoft LLC Receives Small Business Biodefense Grant Award Molsoft LLC received a Small Business Biodefense Program award from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, for the project entitled .Rational Design of Inhibitors of Yersinia pestis EF-Tu.. Molsoft and its research partners at the University of California, Irvine and Chemical Diversity Labs, Inc., San Diego, propose to develop a new class of antibacterial agents active against Category A pathogens likely to be used by bioterrorists including those causing plague, anthrax, cholera, and typhoid fever. Furthermore, the project proposes to develop design principles that will be useful in developing agents less susceptible to the problem of rapidly emerging antibiotic drug resistance.
18 June 2003.Mpex Pharmaceuticals and Molsoft announce collaboration for the structure-based design of new antibacterial compounds. Mpex Pharmaceuticals Inc. (“Mpex”) and Molsoft, LLC (“Molsoft’) have announced a collaboration to rationally design new antibacterial agents based on the refinement of a 3-D molecular structure of a membrane protein target, the functional characterization of its surfaces, and the application of predictive algorithms ..more..
June 16, 2003 Molsoft LLC Receives Phase II STTR Grant Award to Continue Developing Thyroid Receptor Antagonists Molsoft LLC received a Phase II STTR award from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, for continuation of the "Rational Development of Thyroid Receptor Antagonists. project. In Phase I, Molsoft and its collaborators at the NYU School of Medicine and the NYU Department of Chemistry achieved proof of concept. Molsoft.s virtual ligand screening technology was used to discover 14 small molecule thyroid receptor antagonists displaying extreme structural diversity with IC50s ranging from 4 to 30 microM. Additionally, the test-case lead optimization scheme designed in Phase I based on generating focused virtual libraries of molecules easily amenable to organic parallel synthesis resulted in the rapid identification of second generation hits with IC50 in the nanomolar range. In Phase II, Molsoft and its NYU research partners propose to conduct full-scale optimization cycles of selected hits identified in Phase 1 in order to produce low nanomolar hits and to evaluate those hits using computational tools, in vitro characterization, and preliminary animal studies. May 20th-21st 2003 Molsoft LLCConducts Annual Spring Training CourseOn the 20-21st May 2003 conducted an ICM workshop entitled "In Silico Drug Discovery". The workshop was held at Molsoft LLC La Jolla.
2002 21 October 2002. Molsoft to Evaluate Novel Scaffolds for PDF Inhibitor Program Molsoft LLC, a La Jolla based company providing new, breakthrough technologies in computational chemistry and biology, and GeneSoft Pharmaceuticals Inc., a specialty pharmaceutical company headquartered in South San Francisco, announced that they have signed a collaborative agreement to evaluate inhibitors of peptide deformylase (PDF), an essential bacterial metalloenzyme and novel antibiotic target ..more... 26 August 2002. Molsoft Conducts Training Course/ Workshop in La Jolla, CA Molsoft conducted an intensive 2-day training course/workshop on the ICM suite of products at La Jolla, CA. The lecture and hands-on demonstrations covered topics of interest to computational chemists and biologists in the area of drug discovery. The topics included molecular graphics, animation, bioinformatics, homology, protein modeling, docking and ICM command language for expert users. The attendance was international with scientists coming from Asia and Europe as well as from various parts of the US. The attendees were interested in having future courses, both at the basic and at the advanced levels. One of the attendees from Australia who is very well known in the modeling field for his early work in structural bioinformatics, Dr. Jiri Novotny (Consultant for Biocomputing and Bioinformatics), said, "The course was well organized and presented the participants with two full days of new and efficient tools applicable to the most pressing problems of current structural biology and bioinformatics: structural/functional annotation of genomic data, analysis of protein surfaces, ligand binding sites, virtual ligand screening, structure derivation, regularization and model building". He continued on to say, "Perhaps the most impressive aspect of the workshop was the skill, dedication and the highest professional standard of the scientific team established at Molsoft by Prof. Abagyan. In hands-on session at computer screens the participants were encouraged to ask questions and bring out problems that were answered and solved immediately by the whole team including themselves. It was an invaluable practice and a good demonstration of the speed and versatility of the newest ICM version."
About the training course, Dr. Maxim Totrov, co-founder and Principal Scientist at Molsoft said, "The course provided us with a vital opportunity to meet members of the growing community of ICM-users and bring them up-to date with the latest developments in ICM. It was exciting to see first-time users perform complex molecular modeling tasks such as protein-ligand docking after only a few hours of training. These workshops are geared towards helping our customers utilize fully the power of ICM molecular modeling suite in their everyday work." 22 August 2002. Molsoft Participates in the Annual Symposium of the Protein Society in San Diego
"We enjoyed talking to numerous visitors to our booth," said Dr. Lalitha Subramanian, Director of Contract Research for Molsoft, "many of whom were extremely excited to see ICM's new GUI interface." She added, "Our science has always been strong and well validated. Now, with the added power of a very user friendly interface, ICM will be the choice for most researchers in the academic and commercial fields." Molsoft also participated in the Beyond Genome 2002 conference held in June of this year and will be presenting at the BioITWorld conference to be held in November. Molsoft LLC Receives Phase II SBIR Grant Award May 21, 2002 Molsoft received a Phase II SBIR award from the Department of Energy for continuation of the "GAP: Genomics Annotation Platform" project. In Phase I Molsoft used its many years of experience in developing molecular visualization and manipulation software to built the computational tools central to the functionality of the GAP. In Phase I, Molsoft successfully used GAP to predict the function of uncharacterized genes. In Phase II, Molsoft will optimize the existing tools and develop an efficient graphical user interface while adding a system for automatic updates to GAP. When completed, the Molsoft GAP will provide an online research platform allowing users from the pharmaceutical industry to access Molsoft's state-of-the-art computational biology technology and to use that technology for extracting meaningful information from the human genome project and from other major, international sequencing efforts. March 2002 Molsoft received a Phase 1 SBIR grant from the National Institutes of Health, National Human Genome Research Institute for its project entitled "Sequence/Structure Annotation of Protein Families." The goal in this project is analyzing in silico well known protein families in order to identify which family members could be good therapeutic targets and how pharmacogenomics strategies can be devised to better design drugs targets at these proteins.
2001 August 2001 Molsoft and Plexus Vaccine Inc.entered into a licensing agreement to discover and commercialize new interventional strategies for global infectious diseases, for drug-resistant microbes, and for chronic diseases associated with cryptic pathogens. Plexus will use the Molsoft ICM software suite to develop Virtual Epitope databases of molecular disease targets for in silico design of structural mimics that can be readily synthesized, tested, and formulated as vaccines ..more.. August 2001 Molsoft received a Phase 1 SBIR grant from the Department of Energy for its project entitled "GAP: Genomics Annotation Platform." The goal in this project is to develop bioinformatics tools used for predicting the function of uncharacterized genes. May 2001 Molsoft and HTS Biosystems, Inc. (HTS) entered into collaboration for Molsoft to develop software modules for instrument control, data collection, local visualization, and analysis of data generated by HTS' Surface Plasmon Resonance (SPR) instruments. April 2001 Molsoft LLC and Chemical Diversity Labs, Inc. (CDL), San Diego, CA, formed a strategic alliance to provide joint chemistry and computational modeling services to their customers. Molsoft will use known three-dimensional structures of drug targets as the starting point for the rational selection process. The Molsoft modeling by homology technology will be applied in cases when the structure is not available. CDL will give Molsoft an access to its collection of over 250,000 diverse purified small molecules already available for biological screening. February 2001 Molsoft and Biovitrum AB, a subsidiary of Pharmacia & Upjohn AB, entered into an agreement to co-develop a Chem-Informatics Client System. Molsoft and Biovitrum will use Molsoft's proprietary programming languages and libraries to develop the software, which will be called BeeHive and will function as a program manager and database interface for chemical searches, analysis, and integration.
2000 November 2000 Molsoft has moved to a new location, click the press release for more details. October 2000 Molsoft and Syrrx, Inc., a pioneer in the field of structural proteomics, entered into a strategic alliance to accelerate structure-guided drug discovery through the combination of Molsoft's Virtual Ligand Screening (VLS) technology and other computational biology technologies with Syrrx's high-throughput structural proteomics platform. ..more.. September 2000 Molsoft received a Phase 1 STTR grant from National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases for its project entitled "Rational Development of Thyroid Receptor Antagonists." The goal of this project is to discover and optimize small molecule antagonists of the thyroid hormone receptor. Molsoft will work with the New York University School of Medicine to complete the project. September 2000 Molsoft LLC announced the relocation of its headquarters and commercial development operations to an expanded facility in La Jolla. The new facility will accommodate several expanded programs, including the continued refinement of ICM 2.8, the expansion of software sales and the addition of new products and in-house services. The new facilities include 3500 square feet of computer laboratory, research, training, and office space in close proximity to The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF), both of whom have research collaboration agreements with Molsoft. September 2000 Molsoft LLC announced its first shipment of the Molsoft BioPackage to Hitachi, Ltd. for distribution in Japan. During the two-year Distribution Agreement, which became effective June 1, 2000, Hitachi will be the exclusive distributor of Molsoft's BioPackage in Japan. Hitachi plans to market the software to Japanese corporations, universities, and laboratories. Molsoft's computer software provides novel computational and informational technologies for biomedicine including genomics and drug discovery. ..more.. April 2000 Molsoft and The Genomics Institute of the Novartis Research Foundation (GNF) have entered into a Research Collaboration Agreement. The collaboration will focus on the further development of computational biology tools for functional and structural annotation of new genomic sequences, protein modeling, and virtual ligand screening. Molsoft will provide its ICM software for research in functional and structural annotation of new genomic sequences, protein modeling and lead discovery at GNF, which will provide GNF researchers with an accurate, speedy and flexible method for structural annotation and protein structure modeling. Molsoft will grant GNF a nonexclusive license to use Molsoft databases and software in gene discovery, functional genomics, and drug discovery, and GNF will supply support for personnel and computer facilities to be used in the joint tool development projects ..more.. July 2000 Molsoft LLC and The Scripps Research Institute (TSRI), a private, non-profit research organization engaged in basic biomedical research, announced the formation of research collaboration. During the term of the agreement, TSRI and Molsoft will collaborate on defined joint projects involving the functional and structural annotation of new genomic sequences and protein modeling. For the joint projects, Molsoft will grant TSRI a nonexclusive and restricted license to use Molsoft databases and software in gene discovery, functional genomics and drug discovery, and TSRI will supply personnel and computer facilities for use in the joint projects. ..more..
1999 November 1999 Molsoft LLC and eBioinformatics, Inc. announced the formation of an alliance in which Molsoft will provide its ICM software for incorporation into eBioinformatics, Inc. flagship product BioNavigator. The Molsoft-ICM suite of computational biology tools will provide BioNavigator users with access to the latest and most powerful algorithms. This alliance will give scientists new opportunities based on the power of Molsoft's ICM software and the convenience of BioNavigator's web-based bioinformatics workspace ..more..
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On January 25th-27th 2006, a 3-day ICM Workshop was held at Molsoft's La Jolla
offices. The first two days of the workshop covered all aspects of protein
structure and drug discovery including sequence analysis, protein modeling,
small molecule docking, protein-protein docking, cheminformatics and QSAR. The
third day was dedicated to advanced ICM training including the ICM command
language, scripting, loop modeling and flexible receptor docking. The course was conducted by Prof. Ruben Abagyan (The Scripps Research Institute) and
Dr. Maxim Totrov (Principal Scientist - Molsoft).
The new version, ICM 3.0, was introduced at the course and was well accepted as
an extremely user-friendly interface by the attendees. This version, which also
has stereo viewing mode that works with VRex glasses on Linux and Windows
platforms, was welcomed by all the participants as an efficient and low cost
alternative to existing stereo viewing tools.
Molsoft is pleased to announce its participation at the Protein Society's 16th
Annual Symposium held at the Marriott in San Diego from August 17-21, 2002.
Attendance was estimated at around 1300. Molsoft's exhibit was designed to
inform Protein Society attendees about the latest technology available from
Molsoft including its recent version of a new graphical interface which enables
Molsoft's ICM software easier to use than ever before.
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