Research Summary

My research and training efforts are geared toward applications of computation to drug discovery, with an emphasis on making use of multiple methods and data types, exploiting synergy between protein structural data, chemical/target annotation information, and ligand binding affinity data. My laboratory has a particular focus on cancer-related therapeutic discovery, as are part of many collaborators that make use of our computational methods.

I have been at the forefront of computer-aided drug discovery (CADD) since the early 1990's, beginning in biotechnology start-ups such as Arris Pharmaceutical and continuing for over 20 years at UCSF. The central areas of research in the lab are: (1) methods for docking small molecules to proteins using empirically derived scoring functions; (2) methods for inducing the shape of a protein binding pocket given the structures and affinities of ligands that bind the pocket competitively; (3) generalized surface-based approaches to computing molecular similarity, both among small molecules and among proteins; and (4) approaches for very fast conformational search, including macrocycles, optionally including context from NMR restraints or fitting X-ray density maps. All of the approaches share their roots in the use of sophisticated computational algorithms involving object representation, function optimization, and search. My formal training at the PhD-level in Computer Science has been a distinct advantage in this work.

The following highlight recent work that is particularly relevant to the themes within the lab: synergy of diverse methods and data types for drug discovery. (1) We made use of a fast generalization of our ligand-based similarity approach (looking at small molecule surfaces from the outside) to instead quantify the similarity of protein binding sites (by looking at binding cavities from the inside). This approach (called PSIM) was shown to support characterization of proteins of unknown function. Using PSIM combined with other data, we developed hybrid approaches for (2) ligand affinity prediction, (3) prediction of polypharmacology, and (4) bioactive small molecule pose prediction.

Research Funding

  • January 1, 2013 - March 31, 2021 - Binding-Site Modeling with Multiple-Instance Machine-Learning, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM101689
  • July 1, 2005 - June 30, 2014 - Data-Driven Approaches for Molecular Docking, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM070481
  • August 5, 1999 - September 29, 2012 - Cancer Center Support Grant, Co-Investigator. Sponsor: NIH/NCI, Sponsor Award ID: P30CA082103
  • January 1, 2013 - March 31, 2021 - Binding-Site Modeling with Multiple-Instance Machine-Learning, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM101689


University of Minnesota, St. Paul, MN, BS, 1986, Biochemistry
University of Minnesota, Minneapolis, MN, BS, 1986, Computer Science
Carnegie Mellon University, Pittsburgh, PA, MS, 1989, Computer Science
Carnegie Mellon University, Pittsburgh, PA, PhD, 1991, Computer Science

Honors & Awards

  • 2010
    Levinthal Lecturer, Eleventh International CUP Symposium in Molecular Modeling

Selected Publications

  1. Brueckner AC, Deng Q, Cleves AE, Lesburg CA, Alvarez JC, Reibarkh MY, Sherer EC, Jain AN. Conformational Strain of Macrocyclic Peptides in Ligand-Receptor Complexes Based on Advanced Refinement of Bound-State Conformers. J Med Chem. 2021 03 25; 64(6):3282-3298.  View on PubMed
  2. Jain AN, Cleves AE, Brueckner AC, Lesburg CA, Deng Q, Sherer EC, Reibarkh MY. XGen: Real-Space Fitting of Complex Ligand Conformational Ensembles to X-ray Electron Density Maps. J Med Chem. 2020 09 24; 63(18):10509-10528.  View on PubMed
  3. Cleves AE, Jain AN. Structure- and Ligand-Based Virtual Screening on DUD-E+: Performance Dependence on Approximations to the Binding Pocket. J Chem Inf Model. 2020 09 28; 60(9):4296-4310.  View on PubMed
  4. Cleves AE, Johnson SR, Jain AN. Electrostatic-field and surface-shape similarity for virtual screening and pose prediction. J Comput Aided Mol Des. 2019 10; 33(10):865-886.  View on PubMed
  5. Jain AN, Cleves AE, Gao Q, Wang X, Liu Y, Sherer EC, Reibarkh MY. Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen. J Comput Aided Mol Des. 2019 06; 33(6):531-558.  View on PubMed
  6. Cleves AE, Jain AN. Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose. J Comput Aided Mol Des. 2018 07; 32(7):731-757.  View on PubMed
  7. Cleves AE, Jain AN. ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs. J Comput Aided Mol Des. 2017 May; 31(5):419-439.  View on PubMed
  8. Cleves AE, Jain AN. Extrapolative prediction using physically-based QSAR. J Comput Aided Mol Des. 2016 Feb; 30(2):127-52.  View on PubMed
  9. Cleves AE, Jain AN. Knowledge-guided docking: accurate prospective prediction of bound configurations of novel ligands using Surflex-Dock. J Comput Aided Mol Des. 2015 Jun; 29(6):485-509.  View on PubMed
  10. Jones DA, Rathod KS, Gallagher S, Jain AK, Kalra SS, Lim P, Crake T, Ozkor M, Rakhit R, Knight CJ, Iqbal MB, Dalby MC, Malik IS, Whitbread M, Mathur A, Redwood S, MacCarthy PA, Weerackody R, Wragg A. Manual Thrombus Aspiration Is Not Associated With Reduced Mortality in Patients Treated With Primary Percutaneous Coronary Intervention: An Observational Study of 10,929 Patients With ST-Segment Elevation Myocardial Infarction From the London Heart Attack Group. JACC Cardiovasc Interv. 2015 Apr 20; 8(4):575-84.  View on PubMed
  11. Taylor RJ, Saloura V, Jain A, Goloubeva O, Wong S, Kronsberg S, Nagilla M, Silpino L, de Souza J, Seiwert T, Vokes E, Villaflor V, Cohen EE. Ex vivo antibody-dependent cellular cytotoxicity inducibility predicts efficacy of cetuximab. Cancer Immunol Res. 2015 May; 3(5):567-74.  View on PubMed
  12. Rathod KS, Jones DA, Bromage DI, Gallagher SM, Rathod VS, Kennon S, Knight C, Rothman MT, Mathur A, Smith E, Jain AK, Archbold RA, Wragg A. Radial primary percutaneous coronary intervention is independently associated with decreased long-term mortality in high-risk ST-elevation myocardial infarction patients. J Cardiovasc Med (Hagerstown). 2015 Mar; 16(3):170-7.  View on PubMed
  13. Jones DA, Howard JP, Rathod KS, Gallagher SM, Knight CJ, Jain AK, Mathur A, Mohiddin SA, Mills PG, Timmis AD, Archbold RA, Wragg A. The impact of socio-economic status on all-cause mortality after percutaneous coronary intervention: an observational cohort study of 13,770 patients. EuroIntervention. 2015 Feb; 10(10):e1-8.  View on PubMed
  14. Jain AK, Wen JX, Arora S, Blomenkamp KS, Rodrigues J, Blaufuss TA, Liou V, Burrin DG, Long JP, Teckman JH. Validating hyperbilirubinemia and gut mucosal atrophy with a novel ultramobile ambulatory total parenteral nutrition piglet model. Nutr Res. 2015 Feb; 35(2):169-74.  View on PubMed
  15. Cleves AE, Jain AN. Chemical and protein structural basis for biological crosstalk between PPARa and COX enzymes. J Comput Aided Mol Des. 2015 Feb; 29(2):101-12.  View on PubMed
  16. Soares KC, Foley K, Olino K, Leubner A, Mayo SC, Jain A, Jaffee E, Schulick RD, Yoshimura K, Edil B, Zheng L. A preclinical murine model of hepatic metastases. J Vis Exp. 2014 Sep 27; (91):51677.  View on PubMed
  17. Kapil V, Jain AK, Lobo MD. Renal Sympathetic Denervation - A Review of Applications in Current Practice. Interv Cardiol. 2014 Mar; 9(1):54-61.  View on PubMed
  18. Yera ER, Cleves AE, Jain AN. Prediction of off-target drug effects through data fusion. Pac Symp Biocomput. 2014; 160-71.  View on PubMed
  19. Rathod KS, Jones DA, Rathod VS, Bromage D, Guttmann O, Gallagher SM, Mohiddin S, Rothman MT, Knight C, Jain AK, Kapur A, Mathur A, Timmis AD, Amersey R, Wragg A. Prognostic impact of anaemia on patients with ST-elevation myocardial infarction treated by primary PCI. Coron Artery Dis. 2014 Jan; 25(1):52-9.  View on PubMed
  20. Spitzer R, Cleves AE, Varela R, Jain AN. Protein function annotation by local binding site surface similarity. Proteins. 2014 Apr; 82(4):679-94.  View on PubMed

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