Mechanisms underlying biology at a molecular level are explored through identifying and/or mapping the interactions
of proteins with other proteins, nucleic acids, ligands. The methods/tools used are computational and combine
representations at various levels, from the coarse-grained to the fully atomistic. The work builds upon foundations
that are rooted in rigorous computational biochemistry benchmarked extensively against available experimental data. Simulations complement extensive collaborations with experimental laboratories to provide incisive insights into biology at an atomic level. The group’s current research focuses on several bimolecular mechanisms including those associated with the p53 pathway, kinases, translation initiation, antimicrobials and basic computational biophysical chemistry.
The toolbox used consists of: construction of models based on “imagination with a whiff of hand-waving”, homology modelling, molecular dynamics, energy landscapes, reaction paths, ligand-protein/protein-protein dockings including virtual screening, molecular design, machine learning/AI. The group couples the molecular underpinnings of biomolecular regulation with ligand/drug discovery and protein/peptide design both from a therapeutic as well as a (bio)technological perspective.
An extensive program with Sir David Lane combining computer modeling, biophysics, crystallography, molecular/cell biology, investigating the relationship between structural-functional aspects of the p53 family has revealed interesting nuances about the p53 pathway. These have guided us in designing a set of novel constrained (stapled/stitched) peptides whose ability to enter cells and specifically target the p53-MDM2 axis with nanomolar affinities, thus activating p53, has opened a new avenue for designing therapeutics (highlighted in Nature Med 19; 120; 2013). A major effort currently underway (Org Biomol Chem 2018 16 389) is focused on understanding the mechanism of cellular permeabilization and nuclear entry of these peptides and subsequently in using these peptides as vehicles for delivering cargo into cells (Bioorg Med Chem. 2018 26 2807). In parallel a multidisciplinary effort with the pharma company Ipsen has resulted in the successful development of stapled peptides against eIF4E to inhibit translation initiation for a range of cancers (Chem Sci 2019 in press). A breakthrough has recently been achieved in the successful design of nonhelical stapled peptides which suddenly opens new avenues for targeting and expanding the traditionally undruggable universe of protein-protein interactions (PNAS 2018; Chem Sci 2018b). This collaboration has brought in partners from local organizations, the Universities of Edinburgh, Cambridge, Dundee, Southampton, Newcastle and Harvard and with the pharma Ipsen and MSD.
In parallel, efforts are underway to understand the mechanisms of the translational initiation cascade and inhibit a key component in this pathway, eIF4E, which offers opportunities as a major target for therapeutic intervention in several cancers. Recent design efforts combined with extensive biophysical and structural analyses have led to the design of low nanomolar inhibitory stapled peptides. The recent developments and the excitement generated in the p53 field have been outlined in articles in Nature Reviews Drug Discovery, Nature Reviews in Cancer, Nature Reviews in Clinical Oncology that has been published by the joint efforts of teams from Singapore, Karolinska, Cambridge & Harvard Universities. The program is supported by generous funding from A*STAR and pharma.
A highly successful interdisciplinary program with the group of Prof Beuerman at the Singapore Eye Research Institute and researchers at IMB, ETC, Nanyang Technological University, National University of Singapore, Singapore General Hospital and Duke-NUS has resulted in the design of novel antimicrobials (Biochim Biophys Acta Biomembr. 2018 1860 1517; Proteins 2018 86 548). These molecules target membranes with rapid killing times, are non-toxic to human cells and appear to avert resistance in bacteria. The greater anionicity of the bacterial membranes appears to be responsible for the rapid adsorption and hence killing of the former and for the non-toxicity of these cationic molecules; the inability of bacteria to easily remodel their membranes possibly leads to their susceptibility (J Phys Chem B 2018 122 8698). The molecules work against a range of gram-positive and gram-negative organisms including resistant MRSA. A unique platform outlining the first reported in-membrane fragment based design method has been developed and several patents filed. The project has attracted generous funding from ETPL/A*STAR, NMRC. A spinoff company has been set up (www.sinsalabs.com). We are currently combining simulations with experiments to demonstrate the mechanism of antimicrobial actions and selectivities of novel polymers for wound healing.
In a large translational effort, the group is engaged with experimentalists (Dr Scaltriti, MSKCC), Dr Uttam Surana (IMCB) and clinicians Dr Daniel Tan (GIS, SGH, NCC Singapore) studying the effects of small molecule and antibody based therapies for cancers (Cancer Cell 2016). This work is now directed at the putative effects of mutations and SNPs (Chem Sci 2018a; J Chem Inf Model 2018 in press) in patients on drugs used in the clinic.
The translational and clinical focus of the group is backed by rigorous investigations into the fundamental questions
regarding the modulation of biomolecular function, developments of analytical processes, relationships between flexibility, thermodynamics, kinetics and function in biomolecules (J Chem Phys 2018 148 104902; J Chem Theor Comput 2018 14 3920; ACS Omega 2018 3 2498; Proteins 2018 86 301; Oncotarget 2017 8:112825)
The virtual screening/peptide design efforts of the group are in extensive collaborations in A*STAR (ETC, IMCB, IMB, SIGN, p53Lab, MEL, SBIC, ICES), the hospitals in Singapore, research centres (NCC, CSI, LKC), universities (NUS, NTU, Duke-NUS) and organizations elsewhere (Univ of Cambridge, Karolinska Instt) (eg J Med Chem 2018). Programs that combine the strengths of various institutes, hospitals and universities in Singapore towards peptide engineering, wound healing, precision medicine, bioimaging and small molecule discovery are generously funded by the Industry Alignment Fund Pre-Positioning grant. A major effort is underway together with pharma (MSD) and teams from p53lab, ICES to investigate the cellular permeability
of drugs (Bioorg Med Chem. 2018 26 2807). Combining a new yeast-based platform and modelling with colleagues in
A*STAR at IMCB and BTI have resulted in a novel potential therapeutic for wet-AMD which is now being pursued in a
new spinoff Sinopsee Therapeutics.
The success of the group has encouraged several experimental groups worldwide to participate with us. These have also resulted in joint graduate programs with various universities including NCBS, IISc, Southampton, Manchester, Dundee, Edinburgh, Liverpool, Essex.
Chandra Verma joined the Bioinformatics Institute (BII) A*STAR, Singapore, in November 2003. He heads the division of Biomolecular Modelling and Design and leads a group that applies physics based models to understand the links between protein sequence, structure and biological function. His group works closely with experimental laboratories where the hypotheses generated are tested. In addition, the group is also involved in designing peptides and small molecules (through virtual screening) both for interrogating biology as well as for therapeutic purposes. Prior to joining Singapore, he worked at the Structural Biology Laboratory in York, UK. He obtained his undergraduate degree at the Indian Institute of Technology, India and his D. Phil at the University of York.Group Members