Focus: Drug Metabolism/Structural Biology
- Ph.D., University of Nottingham, UK
- M.Sc., University of Nottingham, UK
- B.Pharm., Karnatak University, India
- Molecular Foundations of Drug Action
- Scientific Literature Evaluation
- Pharmaceutical Sciences Research Experience
- M.S. Pharmaceutical Sciences Admissions Committee
- Genetic polymorphisms in drug metabolizing cytochrome P450 (CYP) enzymes are important determinants of inter-individual variability in drug response leading to adverse drug reactions and drug-drug interactions. Despite the abundant structural and functional information available regarding multiple human CYPs, the structural basis of single nucleotide polymorphism has remained scant. Using X-ray crystallography, biophysical and computational methods, the long-term goal of my research include studying the influence of genetic polymorphisms on the activity of CYPs. Current research is focused on CYP2C9 variants.
- Out of the 57 human CYPs, a number of enzymes have been designated as “orphans” since their functional role and specific substrates are unknown. Another research interest of the lab is to characterize CYPs with unknown endogenous substrates or functions. The research involves studying structure and function of CYP2U1.
HONORS AND ACHIEVEMENTS
- Best Abstract Award - American Society for Pharmacology and Experimental Therapeutics, Drug Metabolism Division. Experimental Biology Meeting 2012, San Diego, CA
- University of Connecticut, Storrs, CT
- University of California, San Diego, CA
- Hauptman-Woodward Institute (University at Buffalo), Buffalo, NY
PROFESSIONAL ORGANIZATION MEMBERSHIP
- American Society for Pharmacology and Experimental Therapeutics (ASPET)
- American Society for Biochemistry and Molecular Biology (ASBMB)
- International Society for the Study of Xenobiotics (ISSX)
- “Crystal Structure of CYP2B6 in Complex with an Efavirenz Analog: From Plasticity to PI Interactions in CYP2B Enzymes”. The 21st North American International Society for the Study of Xenobiotics Meeting, Providence, RI. September 24-28, 2017.
- “Single Nucleotide Polymorphisms in Cytochromes P450 2C9: Utility of Crystal Structures in Understanding Drug Metabolism and Pharmacogenomics”. State University of New York College of Nanoscale Science and Engineering, Albany, NY. August 28, 2017.
- “Crystal Structures of CYP2C9, CYP2C9*3 and CYP2C9*30 in Complex with Multiple Losartan Molecules Reveal a Peripheral Binding Site and Alternate Active Site Orientations”. The 21st International Symposium on Microsomes and Drug Oxidations, UC Davis, CA. October 2-6, 2016.
Manish B. Shah, Qinghai Zhang and James R. Halpert. Crystal Structure of CYP2B6 in complex with an Efavirenz Analog. International Journal of Molecular Sciences. 2018. 19: 1025.
Keiko Maekawa, Motoyasu Adachi, Yumiko Matsuzawa, Qinghai Zhang, Ryota Kuroki, Yoshiro Saito, Manish B. Shah. Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9. Biochemistry. 2017. 56: 5476–5480.
Manish B. Shah, Jingbao Liu, Qinghai Zhang, C. David Stout, James R. Halpert. Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity. ACS Chemical Biology. 2017. 12: 1204-10.
Manish B Shah, Hyun-Hee Jang, P. Ross Wilderman, David Lee, Sheng Li, Qinghai Zhang, C. David Stout, and James R. Halpert. Effect of Detergent Binding on CYP2B4 Structure as Analyzed by X-ray Crystallography and Deuterium-Exchange Mass Spectrometry. Biophysical Chemistry. 2016. 216:1-8.
Manish B. Shah, Jingbao Liu, Lu Huo, Qinghai Zhang, M. Denise Dearing, P. Ross Wilderman, Grazyna D. Szklarz, C. David Stout, and James R. Halpert. Structure-Function Analysis of Mammalian CYP2B Enzymes using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism. Molecular Pharmacology. 2016. 89: 435-45. (Cover Article)
Jingbao Liu, Manish B. Shah, Qinghai Zhang, C. David Stout, James R. Halpert, and P. Ross Wilderman. Coumarin Derivatives as Substrate Probes of Mammalian Cytochromes P450 2B4 and 2B6: Assessing the Importance of 7-Alkoxy Chain Length, Halogen Substitution, and Non-Active Site Residue Mutations. Biochemistry. 2016. 55: 1997-07.
Manish B. Shah, P. Ross Wilderman, Jingbao Liu, Hyun-Hee Jang, Qinghai Zhang, C. David Stout and James R. Halpert. Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison. Molecular Pharmacology. 2015. 87: 649-59.
Manish B. Shah, Irina Kufareva, Jaime Pascual, Qinghai Zhang, C. David Stout, and James R. Halpert. A Structural Snapshot of CYP2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States. Journal of Pharmacology and Experimental Therapeutics. 2013. 346: 113-120.
P. Ross Wilderman, Manish B. Shah, Hyun-Hee Jang, C. David Stout, and James Robert Halpert. Structural and Thermodynamic Basis of (+)-α-Pinene Binding to Human Cytochrome P450 2B6. Journal of the American Chemical Society. 2013. 135: 10433−40.
Manish B. Shah, Hyun-Hee Jang, Qinghai Zhang, C. David Stout, and James R. Halpert. X-ray Crystal Structure of the Cytochrome P450 2B4 Active Site Mutant F297A in Complex with Clopidogrel: Insights into Compensatory Rearrangements of the Binding Pocket. Archives of Biochemistry and Biophysics. 2013. 530: 64-72.
Haoming Zhang, Sean C. Gay, Manish B. Shah, Maryam Foroozesh, Jiawang Liu, Yoichi Osawa, Qinghai Zhang, C. David Stout, James R. Halpert, Paul F. Hollenberg. Potent Mechanism-Based Inactivation of Cytohcrome P450 2B4 by 9-Ethynylphenanthrene: Implications for Allosteric Modulation of Cytochrome P450 Catalysis. Biochemistry. 2013. 52: 355-64.
Manish B. Shah, P. Ross Wilderman, Jaime Pascual, Qinghai Zhang, C. David Stout and James R. Halpert. Conformational Adaptation of Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4 Revealed Upon Binding Multiple Amlodipine Molecules. Biochemistry. 2012. 51: 7225-38.
Jyothi C. Talakad, Manish B. Shah, Greg S. Walker, Cathie Xiang, James R. Halpert, Deepak Dalvie. Comparison of In Vitro Metabolism of Ticlopidine by Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4. Drug Metabolism and Disposition. 2011. 39: 539-50.
Manish B. Shah, Jaime Pascual, Qinghai Zhang, C. David Stout and James R. Halpert. Structures of Cytochrome P450 2B6 Bound to 4-Benzylpyridine and 4-(4-Nitrobenzyl) pyridine: Insight into Inhibitor Binding and Rearrangement of Active Site Side Chains. Molecular Pharmacology. 2011. 80: 1047-55. (Cover Article)
P. Ross Wilderman, Manish B. Shah, Tong Liu, Sheng Li, S Hsu, Arthur G. Roberts, David R. Goodlett, Qinghai Zhang, Virgil L. Woods, Jr., C. David Stout, and James R. Halpert. Plasticity of Cytochrome P450 2B4 as Investigated by Hydrogen-Deuterium Exchange Mass Spectrometry and X-Ray Crystallography. Journal of Biological Chemistry. 2010. 285: 38602-11.
Sean C. Gay, Manish B. Shah, Jyothi C. Talakad, Keiko Maekawa, Arthur G. Roberts, P. Ross Wilderman, Ling Sun, Jane Y. Yang, Stephanie C. Huelga, Wen-Xu Hong, Qinghai Zhang, C. David Stout, and James R. Halpert. Crystal Structure of a Cytochrome P450 2B6 Genetic Variant in Complex with the Inhibitor 4-(4-Chlorophenyl) imidazole at 2.0-Å Resolution. Molecular Pharmacology. 2010. 77: 529-38. (Cover Article)
Manish B. Shah, Cheryl Ingram-Smith, Leroy L. Cooper, Jun Qu, Yu Meng, Kerry S. Smith and Andrew M. Gulick. The 2.1 Å Crystal Structure of an Acyl-CoA Synthetase from Methanosarcina Acetivorans Reveals an Alternate Acyl-Binding Pocket for Small-Branched Acyl Substrates. Proteins. 2009. 77: 685-98.
Eric J. Drake, Jin Cao, Jun Qu, Manish B. Shah, Robert M. Straubinger, and Andrew M. Gulick. The 1.8 Å Crystal Structure of PA2412, an MbtH-like Protein from the Pyoverdine Cluster of Pseudomonas Aeruginosa. Journal of Biological Chemistry. 2007. 282: 20425-34.
Gareth Hall, Manish Shah, Paul McEwan, Charles Laughton, Malcolm F.G. Stevens, Andrew Westwell, and Jonas Emsley. Structure of Mycobacterium Tuberculosis thioredoxin C. Acta Crystallogr D. 2006. 62: 1453-57.
Manish Shah, Geoffrey Wells, Tracey D. Bradshaw, Charles A. Laughton, Malcolm F.G. Stevens and Andrew D. Westwell. Antitubercular Properties of Substituted Hydroxycyclohexadienones. Letters in Drug Design and Discovery. 2006. 3: 419-23.
Tracey D. Bradshaw, Charles S. Matthews, Jennifer Cookson, Eng hui Chew, Manish Shah, Kevin Bailey, Anne Monks, Erik Harris, Andrew D. Westwell, Geoffrey Wells, Charles A. Laughton and Malcolm F.G. Stevens. Elucidation of thioredoxin as a Molecular Target for Antitumor Quinols. Cancer Research. 2005. 65: 3911-19.
CONFERENCES AND PRESENTATIONS
Shah MB. 16th Annual International Conference 2018 - "The Road from Nano-medicine to Precision Medicine", Albany NY, September 17, 2018 (invited talk).
Shah MB. Structural Determinants of Substrate Selectivity in Human Cytochromes P450 2C9 and 2C18. Experimental Biology 2018, San Diego CA, April 21-25 (poster presentation).
Shah MB. Structural and Computational Insights into Single Nucleotide Polymorphisms in Cytochrome P450 2C9. 8th Annual ACPHS Research Forum, Albany NY, January 2018 (poster presentation).
HONORS, AWARDS, AND APPOINTMENTS
Member, Editorial Board of Current Metabolomics
Member, Editorial Board of EC Pharmacology and Toxicology