Q&A: Pharmacophore modeling for potential drug discovery

Dr. Apurba K Bhattacharjee, Georgetown University

Q: What are the current approaches to screen for compounds that would fit into a given pharmacophore?
A: Pharmacophore based searching, structure similarity based searching, docking at the active site, dynamic docking and use of machine learning (AI) tools. 

Q: How to choose the 3D pharmacophore model software programs considering parameters either molecular filed or substitution pattern or a combination of both? 
A: There are various functions available in different software. You are to select them based on your specific needs. Discovery Studio (BIOVIA), COMFA (Comparative molecular field analysis (CoMFA) on the training set of active compounds has the predictive ability to test on additional compounds. There are a variety of them available commercially.

Q: How to do a 3D model when no active ligand(s) available for a known target?
A: Some experimental information of a ligand or target active site details should be available. You may hypothetically design a pharmacophore model based on complementary information from the active site of the known target. Use the hypothetical pharmacophore model as template for search of compound databases may enable you to find ligands for the target. You will even be able to identify a few compounds from the search and make a 3D model.

Q: How many compounds does one need for an effective “training set?”
A: If you use statistical methods like Catalyst (Discovery Studio) methods, you should ideally require at least 15 compounds in the training set. If you start with QM (quantum mechanical) approach to develop molecular electrostatic potential profiles, you can perform the task with lesser number known active compounds.

Q: Is it possible to provide complete molecular flexibility to the target protein?
A: Yes. Dynamic docking can be performed. You may also consider water molecules at the active site of the target.

Q: How to address a major limitation of Ligand-based pharmacophore dependence on pre-computed databases that contain a limited number of low-energy conformations per molecule?
A: Most of the procedures for generation of compound databases useful for pharmacophore based (not structure of ligand) search recommends multi-conformer generation of molecules within 0.0-20.0 kcal/mol. Catalyst, Discovery Studio (Biovia) etc already have procedures for such database generation. 

Q: In your examples you have illustrated the use of Pharmacophore in already known and validated receptors. In case if the receptors are not known or validated how does Bioinformactis/AI assist us to discover complete novel receptors and pharmacophore. 
A: Not really. Pharmacophore based procedures are most useful when the receptor structures are not known. Only a handful of active disease specific compounds (15-20) should be enough. Even less number of active compounds are also possible but will have to use QM methods for generation of molecular electrostatic potential (MEP) profiles. The MEP can be an useful guidance for pharmacophore generation even for small training set of active molecules. Approach for Bioinformatics/AI tools are useful only when you have large (really large) number active and inactive compounds in a database. 

Q: From the standpoint of pharmacophores, in your opinion, which is the least and the most favorable rule of the Linpinsky’s rules?
A: From Druglikeness point of view, Lipinsky’s rule is empirical. However, it is very useful when you have a short list of 5-10 lead compounds to promote, the rule is extremely helpful. 

Q: Specificity or Sensitivity? Which one will you prefer for pharmacophore modeling validation?
A: The goal will undoubtedly be specificity.

Q: For unknown target, what would be the average number of molecules needed to build a good pharmacophore model ? Which parameters (e.g. IC50) would be mandatory to build this model?
A: A training set of 15-20 (10 highly potent, 5 intermediately potent, and 5 inactive) molecules should be ideal training set. Any of the experimental data from IC-50, ED-50, LD-50 etc may be used to build a pharmacophore model. 

Q: Which software do you recommend for in silico ADMET property predictions?
A: I cannot recommend any single software. There are many good commercial software available now a days. Even free software are available for downloads. I have used TOPKAT from Discovery Studio many years ago.

Q: Can you please provide a list of general references about the methodology

  • O.A. Gunner. In Pharmacophore, perception, development, and use in drug design. Ed. University International Line (IUL Biotechnology Series), San Diego, pp. 17, 2000.
  • A.R. Leach, V.J. Gillet, R.A. Lewis, R. Taylor. Three-dimensional pharmacophore methods in drug discovery. J. Med. Chem., 53, 539, 2010.
  • A.K. Bhattacharjee, J. A. Geyer, C.L. Woodard, A.K. Kathcart, D.A. Nichols, S.T. Prigge, Z. Li, B.T. Mott, and N.C. Waters. A Three Dimensional In Silico Pharmacophore Model for Inhibition of Plasmodium Falciparum Cyclin Dependent Kinases and Discovery of Different Classes of Novel Pfmrk Specific Inhibitors. J. Med. Chem., 2004, 47, 5418-5426.
  • A.K. Bhattacharjee. In silico 3D pharmacophores for aiding discovery of the Pfmrk (Plasmodium Cyclin-dependent protein kinases) specific inhibitors for therapeutic treatment of malaria. Expert Opinion on Drug Discovery 2007, 2(8):1115-1127.
  • A. K. Bhattacharjee, K. Kuča, K. Musilek, R.K. Gordon. In Silico Pharmacophore Model for Tabun-inhibited Acetylcholinesterase (AChE) Reactivators: a Study of their Stereoelectronic Properties. Chem. Res. Toxicol. 2010, 23, 26-36.
  • A.K. Bhattacharjee, E. Marek, H.T. Le, R.K. Gordon. Discovery of non-oxime reactivators using an in silico pharmacophore model of oxime reactivators of OP-inhibited acetylcholinesterase. European J. Med. Chem, 2012, 49 229-238; 2015, 90, 209-220.

Q: How to find out trend/correlation between biological activity and physicochemical (ADME-Tox) properties of the molecules using 3D modeling?
A: Again you would require experimental data (or reliable in silico ADME-Tox) for a set of at least 15 compounds to create a training set to find out the correlation and trend .

Q: How do you anticipate/address active or potentially genotoxic metabolites?
A: You need to know the metabolites. In order to know the metabolites, you will have to have the knowledge of mechanism of action of the active compounds. Please remember when pharmacophores are generated, metabolites are not considered

Q: How often (percentage wise) does an in silico ‘hit’ translate to biological activity?
A: If iterative processes of refining the pharmacophore, search for databases and in vitro testing are carried out, the chance of a very reliable pharmacophore model could be achieved. 

Q: Given that good antitumor drugs are usually not having a good water solubility, one question here is that through this computer drug discovery technology, we may rule out some good candidates that have good antitumor activity for example but due to its poor water solubility (but this can be improved by formulation), such compounds may be ruled out without further consideration.
A: Yes, you are very correct. That is why a computational chemist should be always in consultation with a medicinal chemist before promoting a lead compound.

Q: Where this database come from?
A: There are many commercial compound databases, such as Maybridge, ChemNavigator, Zinc etc. I have used our own in-house database (WRAIR) of about three hundred thousand compounds.

Q: Can we use electrostatic surface potential predicted from QM method to study ligand-protein interactions? If yes how interpret the results?
A: Absolutely. Molecular electrostatic potential (MEP) profile is the interaction pharmacophore of a compound. You can even calculate MEP in water or other solvents using the dielectric values of solvents.

Q: How people get exposure to Nerve agents these days?
A: Mostly from pesticides and certain kind of insect repellents commonly used crop protections.

Q: Are there any studies on how often in silico screening finds real hits? I have seen a few examples where it worked, but I have seen many more that haven’t. Gives hits that are not active when tested?
A: You see experimental testing is absolutely necessary. Many cases are there in literature where it failed. However, iterative refining of models with testing usually produce good results. Remember in silico approach is another tool only like x-ray crystallography, nmr, spectroscopy etc. 

Q: If a compound has a clogP of 6 or 7, but satisfies all other criteria, should it be excluded right away?
A: It should be tried for in vitro testing before discarding it. Lipinsky’s rule is an empirical rule only not hundred percent guaranteed.

David Preston
David Preston

Chairman

David Preston has had 38 years of healthcare experience with publicky Traded and Private companies in the fields of Phammaceuticals, Animal Health and Biotechnology as a Board Member. The last 30 years of his xperience has been in China, Taiwan and Hong Kong building successful igh growth businesses. David Has been Chaiman and CEO for Greater China for Sanofi and Boehringer – Ingelheim as well as the Janssen Corporation since 1991 in China. During this time he build high Growth ousinesses in China through diversified strategies in Innovative Pharmaceuticals. branded Generics. Biotechnology. and Animal Healthcare.

Key highlights in this period indluded building of the first Westem Multinational Biotechnoloqy C.M.O. facility as well as obtaining the first Test CM.OJ MAHI license. Establishment of a number of High tech Vaccine Plants, and R and D facilities in in the field of Animal Health. Signing and development of numerous JV’s as well as Wholly owned Subsidiaries. Mergers and Acquisitions across Phamaceutical’s. Animal Health. and Biotechnology industries

David’s achievement’s in the Healthcare industry and it Growth and development in China is widely recognized By the Chinese Govemnment and the City of Shanghai In 2013 he was awarded the Silver Magnolia ollowed in 2015 the Gold Magnolia award. This was then followed by being awarded in 2017 the Honorary Citizen of Shanghai by 40th People’s Municipal Congress of Shanghai. David Holds a Business Science Degree

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Filippo
Filippo de Vecchi

Director, Advent Partner

Filippo de Vecchi joined Advent in February 2000. He started in the Advent São Paulo office, then moved to Milan in 2002, in 2012 set up the Advent office in Shanghai and in 2016 set up the Hong Kong office. Before joining Advent, he was a senior consultant with Value Partners, in São Paulo and Milan, focusing on strategy and organization in the automotive, energy, cable and media sectors. He began his career at Wasserstein Perella & Co., working as an analyst in the Mergers and Acquisitions department in London and New York. Filippo holds an undergraduate degree cum laude in Economics, with a major in Business Administration, from the LUISS University and an MBA from Columbia Business School, where he currently serves as a member of the Board of Overseers.

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Andrew Li
Andrew Li

Director, Advent Partner

Andrew Li joined Advent in 2012. He previously worked at Warburg Pincus, HSBC PE, Solera Capital and Credit Suisse where he focused on the retail and consumer, healthcare, industrial, and energy sectors. Andrew has worked in finance and private equity throughout the U.S. and China since 1999. Andrew holds a BA from Middlebury College and an MBA from Harvard Business School.    

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Michael Miltenberger
Michael Miltenberger

Director, Advent Partner

Michael Miltenberger  joined Advent in 2011 as an associate on the healthcare team. Following business school, he rejoined Advent’s Boston office, focusing on healthcare investments. Prior to Advent, Michael was a consultant at McKinsey & Company in their Washington DC office, serving a range of healthcare and private equity clients. Michael earned a BA, cum laude, from Harvard College and an MBA from Harvard Business School, graduating with High Distinction as a Baker Scholar and a Harvey Fellow.

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Masood Tayebi
Masood Tayebi, PhD

Director, Operating Partner

Dr. Masood Tayebi is the Founder of BioDuro. He currently serves as CEO of a nationwide real estate portfolio and is a Partner and Chief Executive Officer of the Bridgewest Group. Prior to BioDuro, Dr. Tayebi was Co-Founder and Chairman of Wireless Facilities, Inc. (NASDAQ: WFI), a global leader in telecommunications outsourcing.

Achievements
  • Co-Founder of Wireless Facilities, Inc.

  • Co-Founder of BioAtla, LLC

  • Recipient of the Ernst and Young 2000 Entrepreneur of the Year award in San Diego

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Kewen Jin
Kewen Jin, PhD

Director, Operating Partner

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Amit patel
Amit Patel

Director, Operating Partner

Amit Patel has twenty years of healthcare industry experience with publicly-traded, private equity-backed, and start-up companies in the capacity of executive, board member, advisor, and investor.  He is currently Executive Chairman of Azurity Pharmaceuticals (a NovaQuest Capital Management portfolio company) and a board member at BioDuro (Advent International portfolio company), Tergus Pharma (Great Point Partners portfolio company) and Calyptus Pharma.  Recently, Amit was SVP & President of Dosage Form Solutions at Capsugel, a KKR portfolio company (purchased from Pfizer in 2011 and sold to Lonza in 2017).   

Prior to Capsugel, he worked at Dr. Reddy’s Laboratories, Inc. as EVP & Head of North America, and SVP & Head of Global Corporate Development & Strategic Planning. Earlier, Amit was VP of Corporate Development at CTIS, Inc., and Co-founder & CEO of MedOnTime, Inc. (acquired by CTIS).  He started his career as a strategy consultant with Marakon Associates. Amit holds an M.B.A. degree from Harvard Business School, a B.S. degree in Economics from the Wharton School of Business, University of Pennsylvania, and a B.A.S. degree in Systems Engineering from the Moore School of Engineering, University of Pennsylvania.

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Haijun Dong
Haijun Dong

Chief Executive Officer

Dr. Haijun Dong currently serves as global CEO of BioDuro-Sundia. He previously was CEO for over 5 years at PharmaBlock Sciences Inc., a public company listed in the Shenzhen Stock Exchange (300725.SZ). The positions he held prior to PharmaBlock includes, among others, Senior Scientist at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut; Senior Principal Scientist at Roche in Nutley, New Jersey; Head of DMPK and Drug Safety at Roche China R&D Company in Shanghai; Chief Operating Officer of Eli Lilly China R&D Center in Shanghai.

Dr. Dong received his PhD in organic chemistry from the University of Washington in Seattle, Washington, and MBA from China Europe International Business School in Shanghai. 

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Teo Nee Chuan
Teo Nee Chuan

Chief Financial Officer

Teo Nee Chuan joined us in May 2021 as chief financial officer. Prior to joining us, he was chief financial officer of Huazhu Group from November 2015 to May 2021, and was the chief financial officer for Rnomac International Limited, from November 2011 to August 2015. Mr. Teo worked in DDB Greater China Group, was appointed as the chief financial officer in September 2009, and was additionally appointed as the director of operations in January 2011. He previously served in Focus Media Group and was appointed as the financial deputy director in June 2007. Prior to that, from September 1994 to May 2007, Mr. Teo worked at Ernst & Young and Ernst & Young Business Services Ltd. in various positions in Kuala Lumpur and Toronto, including as a senior manager in the Transaction Advisory Services. Mr. Teo has been an independent director of 111, Inc. (a company listed on the NASDAQ, ticker symbol: YI) since September 2018. Mr. Teo received his Bachelor of Science in Accounting and Financial Analysis degree from The University of Warwick in the United Kingdom in July 1994. He is a Chartered Certified Accountant in the United Kingdom, who has obtained his qualification in July 1998 from The Association of Chartered Certified Accountants, and is a Certified Public Accountant in the United States and Hong Kong, who has obtained his qualification from American Institute of Certified Public Accountants in May 2002 and Hong Kong Society of Accountants in October 2003, respectively.

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TJ
TJ Deng, PhD

President, Discovery

Dr TJ Deng joined BioDuro in the initial stages of the company and helped BioDuro grow to an industry leading discovery services organization. He established and managed several scientific departments, including DMPK, before transitioning to a leader of the business and operations functions. Prior to joining BioDuro, Dr. Deng spent six years at PPD, in positions with increasing responsibilities from scientist to scientific manager.

Achievements

 

 

  • Developed the extractable/leachable capabilities at PPD
  • 18 years industry experience

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Kent Payne
Kent M. Payne, PhD

Chief Executive Officer

Kent is distinguished as a business operator and leader in areas of sales, commercial manufacturing and product development. He has extensive executive experience in M&A as well as successfully running, start up, growth and turn around businesses. This includes both Fortune 500 and Private Equity environments. He combines strong business leadership, successful P&L track record, and technical background to strategically lead and grow enterprise value across Biotechnology and Pharmaceutical market segments. He has successfully led the geographic expansion of businesses into Europe, Asia, and South America in addition to the United States.  He currently serves as CEO for BioDuro-Sundia, LLC (an Advent International company). He also currently serves as a board member for Goodwin Biotechnologies (a Signet Healthcare company). 

Prior Roles

  • President, Global CMC Solutions BioDuro-Sundia, a global
    CRDMO
  • CEO Socorro Pharmaceuticals, LLC, a generic pharmaceutical
    company
  • President Americas, Qualicaps Inc.(a Mitsubishi Chemical Holdings subsidiary)
  • Principal Consultant and Partner at CoreFactor LLC, providing executive strategic, licensing and operational advisory services to clients.
  • Vice President/General Manager Catalent Pharma Solutions, Inc. (a Blackstone Group company formed in 2007, formerly part of Cardinal Health)
  • Progressive leadership responsibility at: Novartis, Monsanto and G.D. Searle.  

Prior Brand Position

  • Board Advisor Vitruvias Therapeutics
  • Board Member Qualicaps, Inc. (a wholly owned subsidiary of
    Mitsubishi Chemical Holdings)
  • Board member Technophar, Inc. (a wholly owned subsidiary of
    Mitsubishi Chemical Holdings)
  • Board Advisor, Corporate Strategy Office, Life Science Institute
    Inc. (a wholly owned subsidiary of Mitsubishi Chemical Holdings)
  • Non-executive Chair and Board Member PDS Biotechnology·        (PDSB: NASDAQ)

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John Phillips
John Phillips

Vice President, Business Development (US & EU)

Coming soon…

Achievements

 

  • Coming soon…

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Roy Xu
Roy Xu

Chief Strategy Officer

Roy has over 25 years of healthcare industry experience.  He started his career as an orthopedic surgeon.  Roy joined Eli Lilly as a sales rep in 1997.  Since then he has had various roles in market research, business intelligence, BU head, strategy, regional general management, business development etc., both at Eli Lilly and Boehringer Ingelheim (BI).  Roy also spent more than two years in Germany where he was BI’s Director of Corporate Business and Enabling Strategy.

Roy obtained a bachelor’s degree in Clinical Medicine at Zhejiang Traditional Chinese Medicine University, and an MBA from Zhejiang University.

Achievements

 

  • 25 years of healthcare industry experience including Eli Lily and Boehringer Ingelheim. 
  • Former Director of Corporate Business & Enabling Strategy at oehringer Ingelheim in Germany.

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San Diego

San Diego - BioDuro-Sundia

Our San Diego site is our corporate headquarters. The facility is home to BioDuro-Sundia’s drug product development technologies and has 9 GMP clean rooms. Development and manufacturing operations are conducted for projects up to Phase III clinical trials.

Size: 44,000 sq. ft.
Featured capabilites: Tableting, Coating, Hot Melt Extrusion, Spray Dried Dispersion

11011 Torreyana Rd.
San Diego
CA 92121
United States

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Beijing

BioDuro Beijing

Operating since 2006, our Beijing site is home to BioDuro-Sundia’s first wet chemistry operations. With 300 regular fume hoods and 18 scale-up chemistry hoods the Beijing facility houses most of BioDuro’s chemistry operations, while also hosting labs for biology and monoclonal antibody discovery.

Size: 100,000 sq. ft. 
Featured capabilities: Radioactivity Lab, Monoclonal Antibody Discovery, Medicinal Chemistry

No. 29 Life Science Park Road
Changping District Beijing,
102206
P.R. China

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Shanghai-Waigaoqiao

BioDuro- Shanghai Facility

Established in 2012, BioDuro-Sundia’s Shanghai facility has been growing with its departments. The cutting edge facility contains labs for ADME, bioanalysis, in vitro assays and translational research. The site includes a 18,000 sq. ft vivarium and 20,000 sq. ft of office space.

Size: 92,000 sq. ft.
Featured capabilities: Scale-up Chemistry, Discovery Biology, DMPK, In Vivo Pharmacology

No. 233 North Fu Te Road
Waigaoqiao Free Trade Zone
Shanghai, 200131
P.R. China

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Cathy Yen
Cathy Yen

Director, Operating Partner

Cathy joined the Board of Directors of BioDuro-Sundia in 2020, with the Advent-led acquisition of Sundia and creation of BioDuro-Sundia. Prior to that, she was Chairman of the Board at Sundia Meditech Group, where she was the key architect of Sundia’s strategic vision and growth. Under her leadership, Sundia solidified its position as one of the leading pre-clinical CROs in China.

Prior to Sundia, Cathy had a distinguished career as a seasoned venture capitalist, having led numerous investments in high-growth companies in Asia. Cathy served as a Partner of AsiaVest Partners, TCW/YFY Ltd., a global venture capital firm, for over a decade, Vice President at Global Financial Services, Vice President at Crimson Ventures/Chinatrust Bank and Senior Manager at Fortune Capital. She brings over 20 years of experience in corporate finance, accounting, strategic planning and private equity investments. 

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Wuxi

Wuxi - BioDuro

Established in 2019, BioDuro-Sundia’s fully integrated discovery facility located at the heart of Jiangsu Wuxi Life Science & Technology Industrial Park with plans of growing staff to 1000+ scientists.

Size: 300,000 sq. ft.
Featured capabilities:
Discovery Chemistry & Biologics, Biology, DMPK, Pharmacology, CMC Services

no.1699,Huishan avenue
Huishan Economic 
Development Zone,Wuxi
P.R. China

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Hebei

Hebei - Sundia

Established in 2011, this pilot plant this handles mg to kg scale up.

Size: 45,208 sq. ft.

Featured capabilities: SFFS Chemistry: mg to kg scale up
(150 hood)

238 Changjiang Road
Shijiazhuang,
Hebei province
P.R. China

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